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Urinary Tract Infections Caused by Uropathogenic Escherichia coli: Mechanisms of Infection and Treatment Options

Yang Zhou, Zuying Zhou, Lin Zheng and 5 more

International Journal of Molecular Sciences · 2023 · Review · CC BY

doi:10.3390/ijms241310537

Abstract

Urinary tract infections (UTIs) are common bacterial infections that represent a severe public health problem. They are often caused by Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumonia), Proteus mirabilis (P. mirabilis), Enterococcus faecalis (E. faecalis), and Staphylococcus saprophyticus (S. saprophyticus). Among these, uropathogenic E. coli (UPEC) are the most common causative agent in both uncomplicated and complicated UTIs. The adaptive evolution of UPEC has been observed in several ways, including changes in colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. While antibiotic therapy has historically been very successful in controlling UTIs, high recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly reduce the efficacy of these treatments. Furthermore, the gradual global emergence of multidrug-resistant UPEC has highlighted the need to further explore its pathogenesis and seek alternative therapeutic and preventative strategies. Therefore, a thorough understanding of the clinical status and pathogenesis of UTIs and the advantages and disadvantages of antibiotics as a conventional treatment option could spark a surge in the search for alternative treatment options, especially vaccines and medicinal plants. Such options targeting multiple pathogenic mechanisms of UPEC are expected to be a focus of UTI management in the future to help combat antibiotic resistance.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Urinary tract infections (UTIs) are the most common bacterial infections and affect one million people globally each year. Among nosocomial infections, UTIs are second only to lower respiratory tract infections, which represent 24% of such cases in developing countries. A UTI requires the presence of more than 105/mL of bacteria in the urine. The symptoms of UTIs are variable, ranging from no symptoms to a severely unwell patient with a high temperature and, sometimes, secondary bacteremia. UTIs can be divided into three categories: acute pyelonephritis, acute cystitis, and asymptomatic bacteriuria. Pyelonephritis is a type of kidney infection, the symptoms of which include the presence of bacteriuria and pyuria. Cystitis is a type of bladder infection, the symptoms of which include frequent urination, dysuria, suprapubic pain, lower abdominal discomfort, and foul-smelling urine. The vast majority of UTIs present as asymptomatic bacteriuria, primarily affecting the lower urinary tract. In some people, such as pregnant or menopausal women, the elderly, diabetics, prepubertal children, and patients with vesicoureteral reflux, bacteria can ascend to the bladder and kidney, making upper UTIs more likely.

Distressingly, UTIs are not only common but also have a high recurrence rate. Usually, a recurring UTI refers to three or more UTIs within one year, as well as two or more recurrences within six months. The abovementioned population is especially susceptible to chronic recurrent UTIs, which leads to the increased use of antibiotics. Women have a high risk of a UTI over their lifetime, and over 20% experience UTI recurrence in the next 6 months after being cured. Recurrent UTIs can be especially frequent during pregnancy and may cause severe adverse consequences for the mother and infant, including preterm birth. Recurrent UTIs are a common problem in the elderly. Menopausal women are more likely to experience recurrent UTIs, as lower levels of estrogen lead to adverse changes in the urogenital epithelium and urogenital microbiome. In addition, UTIs affect nearly one-third of children within one year of birth, and about 30% develop recurrent UTIs. Among the causative factors, bladder and bowel dysfunction (BBD) and vesicoureteral reflux (VUR) are risk factors for recurrent UTIs, especially when they occur simultaneously. Bacteria re-emerging in the bladder epithelium also cause UTI recurrence.

UTIs are caused by a wide range of pathogens, including Gram-negative and Gram-positive bacteria, as well as fungi. According to the epidemiology of UTIs (Figure 1), uropathogenic E. coli (UPEC) are the main pathogenic factor for UTIs, accounting for about 75% of uncomplicated UTI cases; however, less common pathogens, such as Klebsiella pneumoniae (K. pneumonia), Staphylococcus saprophyticus (S. saprophyticus), Enterococcus faecalis (E. faecalis), group B Streptococcus (GBS), Proteus mirabilis (P. mirabilis), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and other pathogenic bacteria cause opportunistic UTIs. UPEC UTIs account for more than half of complicated UTI cases. Therefore, in patients suffering from UPEC UTI, maintenance therapy is ensured by antibiotic prophylaxis. Furthermore, UTIs need to be treated by surgery in some cases, especially when UPEC UTIs develop into recurrent UTIs. However, invalid traditional treatments, antibiotic resistance, and the trauma of surgery have made seeking alternative and complementary treatments urgent, with vaccines and medicinal plants showing significant potential. Therefore, UTIs are a major challenge faced by humans worldwide, and ascertaining their causes and finding the most effective treatments are crucial.

“In this review, the UPEC of concern are the most common pathogenic pathogen for UTIs. The properties of UPEC are summarized, including adherence, motility, toxin production, metal acquisition, intracellular bacterial communities (IBCs), and the evasion of host immune defenses, which can help to understand the pathogenesis of UPEC UTI. In addition, the treatment of UTIs is described, including conventional drugs and complementary and alternative medicines, as well as the presence of antibiotic resistance and the great potential of vaccines and medicinal plants. Finally, we present an outlook, with the hope that this paper will draw attention to recent advances in the field of UTI therapeutics”.

2. Mechanisms of UPEC UTIs

The urethra has a self-defense function and usually prevents UTIs. The urethral mucosa and epithelial cells can resist the invasion of pathogenic bacteria, maintaining a balance between the urethra and bacteria. However, when the pathogenicity of bacteria is very strong, or the body suffers from external damage, this balance is disturbed, and the defense function of the body is compromised. Subsequently, a series of inflammatory reactions occur in the urinary tract, such as urethritis, cystitis, and pyelonephritis. Certain factors of UPEC often play an important role in these reactions, such as lipopolysaccharides (LPSs), polysaccharide capsules, flagella, outer-membrane vesicles, fimbriae, curli, non-fimbrial adhesins, outer-membrane proteins (OMPs), and iron-acquisition receptors. UPEC are more likely to infect the host from the lower urinary tract. When the impact of UPEC on the body cannot be ignored, the host suffers from a UTI or even more serious disease. Usually, the physiological process of UPEC in the host body can be roughly divided into six steps (Figure 2).

The first step is UPEC-induced periurethral and vaginal invasion and colonization. Various fimbriae and adhesins on the surface of UPEC play a pivotal role in mediating adhesion and colonization. The second step is ascension into the bladder lumen and growth as planktonic cells in the urine. The third step is adherence to the surface and interaction with the defensive system of the bladder epithelium. The fourth step is biofilm formation. UPEC proliferate and accumulate to a certain degree to form the biofilm. The biofilm is important in ensuring that bacterial pathogens can colonize the urinary tract and cause infection. Once the biofilm is formed, it may elude immune defense mechanisms. At the same time, the biofilm also exhibits strong drug resistance, and it is difficult for drugs to penetrate the biofilm, leading to chronic and recurrent UTIs. The fifth step is invasion and replication via the formation of IBCs in the bladder, where quiescent intracellular reservoirs (QIRs) arise in the underlying urothelium. Bacterial replication in these IBCs can easily reach as high as 105 bacteria per cell. Additionally, bacteria in the IBCs undergo morphological changes, emerge from the infected cell, and enter neighboring cells, which spreads the infection. The sixth step is kidney colonization. UPEC destroy host tissues by releasing toxins, causing upper UTIs, and severe cases may lead to dangerous conditions, including bacteremia, septicemia, urosepsis, and even death. These cascade stages occur when UPEC successfully attach to host urothelial cells. In the abovementioned process of UPEC action, adhesins, virulence, IBCs, and other factors have important research significance. In general, the strategies of pathogenesis employed by UPEC include adherence, motility, the acquisition of metals, toxin production, and immune evasion. The bacterial adhesins and their receptors on the host’s cells mediate the processes of bacterial colonization, biofilm formation, replication, secretion of toxins, internalization, and invasion. In this section, we discuss several of the main factors in UPEC pathogenesis, particularly chaperone–usher fimbrial adhesins, to provide a clearer understanding of the pathogenesis of UPEC UTIs.

2.1. UPEC Adhesins

Adhesins, a wide range of adhesive proteins assembled by bacteria, can mediate binding to receptors and the colonization of surfaces. Over the past two decades, the whole-genome sequencing of several standard library UPEC strains has revealed the presence of multiple known and putative adhesins in each strain, some of which have been demonstrated to enhance the ability to colonize the urinary tract (Figure 3). Among these, adhesive fibers called pili or fimbriae have attracted widespread attention. Fimbriae are long fibers that extend beyond the bacterial capsule. In diverse genera of Gram-negative bacteria, a molecular machine known as the chaperone–usher pathway (CUP) mediates the assembly of fimbriae on the bacterial outer membrane. At the tips of fimbriae, adhesins are thought to play an important role in the adherence of bacteria to host epithelial receptors. Each sequenced UPEC strain encodes a multitude of CUP operons. At present, several CUP operons, including Auf, Dr, F1C, S, type 9, type 3, type 1, and P fimbriae, have been recognized in UPEC pathotypes (Figure 3), but of those that are broadly conserved among UPEC isolates, only two (type 1 and P fimbriae) have so far been strongly implicated in UTI pathogenesis. CUP adhesins are known to recognize certain receptors with stereochemical specificity, elucidating causative factors and possible drug mechanisms.

As well-known mannose-sensitive organelles, type 1 fimbriae can generate stable bonds with mannosylated glycoproteins of uroplakins (UPs), as well as N-linked oligosaccharides on α3 and β1 integrins and the pattern-recognition Toll-like receptor 4 (TLR4), all of which are expressed in the urine bladder to cause successful UTIs. FimH as the tip adhesin of type 1 fimbriae encompasses a lectin domain on the N-terminal head and a fimbrin domain on the C-terminal end, which has a pathogen-associated molecular pattern (PAMP) role. As another important fimbrial organelle for UPEC cell adhesion, P fimbriae can bind to α-D-galactopyranosyl-1,4-β-D-galactopyranoside in the globo-series glycolipids, whose tip adhesin is PapG. Therefore, it is important to understand type 1 and P fimbriae and their respective characteristic adhesins.

2.1.1. Type 1 Fimbriae and FimH

Considerable evidence suggests that type 1 fimbriae are a critical virulence factor in UPEC-derived UTIs in humans. In addition, type 1 fimbriae have also been shown to play a critical role in establishing cystitis in an experimental murine UTI model, and they are required for UPEC adherence to human urothelial tissue culture cells. Many studies have found that nearly five hundred right-handed helical rod-shaped type 1 fimbriae exist on the surface of UPEC. Furthermore, they can be up to 2 μm in length and 10 nm in width, which guarantees successful bacterial attachment. Meanwhile, numerous studies have found that over 50% of women with an acute UTI show strong positive type 1 fimbriae via the immunostaining of urine sediments, with results comparable to those obtained in acutely infected mice. Interestingly, a study found that urine decreases the UPEC expression of type 1 fimbriae, which may explain the results above. Normally, type 1 fimbrial adhesin subunits are bound to uroplakin molecules in urothelial cells. After successful binding, the phosphorylation processes follow. During phosphorylation procedures, certain signaling pathways associated with bacterial invasion, apoptosis, and the regulation of intracellular ions of calcium within urothelial cells and tissues are complete. At the same time, the kidney cells secrete Tamm–Horsfall protein molecules into the urine. As an 8.7 kbp operon, fimBEAICDFGH, which encodes type 1 fimbriae, is highly conserved. Accordingly, proteins with various functions are produced: regulatory proteins (FimB and FimE); a major subunit (FimA); minor subunits/adaptor subunits (FimI, FimF, and FimG); a chaperone (FimC); an usher (FimD); and an adhesin (FimH) (Figure 4).

As a distal adhesin subunit of type 1 fimbriae, when FimH attaches to the superficial urothelial receptors, it may lead to inflammatory responses, such as dysuria and other painful symptoms in the urinary tract. Numerous studies have found that the expression of FimH is required for bacterial adherence to human bladder tissue in situ, and the vaccination of mice and cynomolgus monkeys with FimH has protected them against experimental cystitis. Interestingly, the receptor for type 1 fimbriae appears to vary depending on the state of urothelial cell differentiation. In mature superficial umbrella cells, the FimH receptor is the mannosylated uroplakin protein UPIa. After binding to UPIa, the phosphorylation of UPIIIa occurs. UPIIIa is the only one of the four major uroplakins with a potential cytoplasmic signaling domain, leading to increased intracellular calcium and enhanced invasion. However, in vitro studies found that some immature urothelial cells, such as 5637 bladder transitional carcinoma cells, generally do not express uroplakins on the cell surface, while mannosylated α3 and β1 integrins are expressed and have been shown to bind to FimH. Simultaneously, bacterial invasion after FimH binding has been reported to involve components of clathrin-coated pits (for example, the cargo-adaptor protein AP-2). The adhesin subunit of FimH encompasses a lectin domain on the N-terminal head, contributing to fimbrial polymerization by attaching to the related fimbrial subunit. On the other hand, the C-terminal end is a fimbrin domain, which links to superficial glycan molecules acting as the host’s urothelial cell receptors. In addition, several amino-acid residues of FimH have been found to be under positive selection. Further studies have found that FimH mediates pathoadaptive mutations in UPEC clinical isolates. When mutations of these residues occurred, the virulence in a murine model of cystitis was reduced, which suggested that FimH plays an important role in human UTIs in vivo.

2.1.2. P Fimbriae and PapG

The role of P fimbriae in UTIs is complex and has not yet been fully explored, but a substantial amount of evidence demonstrates its importance to UPEC. Several studies have reported that P fimbriae are strongly related to pyelonephritis in children but are not highly expressed in women with acute and recurrent UTIs, only accounting for 40% to 50% in isolates. This is likely due to the occurrence of inflammation in acute pyelonephritis and the reduced requirement for P fimbriae in kidney colonization during severe or recurrent UTIs. The linkage of the overwhelming majority of UPEC on urothelial cells is mediated by P fimbriae. α-D-galactopyranosyl-1,4-β-D-galactopyranoside, present in the globo-series glycolipids including GbO3, GbO4, and GbO5, is the receptor for urothelial cells and links with P fimbriae. In humans who are non-secretors of ABO antigens, P fimbriae receptors are found more abundantly on the surface of the kidneys and lower urogenital tract urothelial cells. Recent studies have revealed that many glyco(galacto)lipids exist on the surface of the kidneys’ urothelial cells, indicating the connection between the tip adhesins of P fimbriae and the superficial di-galactose molecules of glycolipid receptors in the kidneys. The above connection may lead to the production of sphingolipid ceramide molecules, which activate the TLR4 signaling pathway. In addition, sphingolipid ceramide molecules regulate certain immune system responses such as proinflammatory cytokines, chemokines (IL-6 and IL-8), and the activation of some groups of leukocytes. Therefore, the occurrence of inflammation can contribute to the elimination of UPEC cells, but it may also harm kidney tissues, prompting the occurrence of acute pyelonephritis. This could explain why the secretor/non-secretor status of ABO antigens is a significant risk factor for UTIs. However, the chronic inflammatory changes in patients with severe or recurrent UTIs may lessen the requirement for P fimbriae when colonizing the kidney.

The number of papIBAHCDJKEFG—10 kbp operons located on pathogenicity islands (PAIs)—depends on various classes of adhesin subunits (ranging from 9 to 12 genes). Accordingly, P fimbrial proteins with different functions encoded by papIBAHCDJKEFG are produced: a tip adhesin (PapG), adapter proteins (PapF, PapE, and PapK), a major subunit (PapA), and a terminator subunit (PapH). Other proteins encoded by papIBAHCDJKEFG include regulator molecules (PapI and PapB), an usher molecule (PapC), a chaperone molecule (PapD), and a minor subunit (PapJ) (Figure 4). Three alleles of the papG gene (PapGI, PapGII, and PapGIII) are recognized among UPEC pathotypes, which differ in their binding specificity to globosides. Among these, PapGII, the most common in UPEC strains, is identified through its receptor isotype, GbO4, and is required for the establishment of pyelonephritis and bacteremia in mammals. PapGIII, which binds to GbO5, is involved in acute cystitis. A recent clinical study found that horizontally acquired papGII-containing pathogenicity islands underlie the emergence of invasive UPEC lineages. However, in a CBA murine model of infection, a lack of PapGII did not affect pathogenesis. PapGII was found to be unnecessary for robust bladder infection in a primate model of uncomplicated cystitis. Alternative adhesins capable of colonizing the kidney epithelium may have influenced the above studies. Additionally, the GbO4 receptor may not be highly expressed in non-mammals. Live multiphoton studies suggest that P and type 1 fimbriae may work together to colonize renal tubules by promoting bacterial attachment and biofilm growth. Thus, although P fimbriae are not highly conserved and are only expressed in about half of UTI isolates, drugs targeting both type 1 and P fimbriae may provide broad bladder and kidney protection.

2.1.3. Other Fimbriae and Non-Fimbrial Adhesins

The Auf fimbriae are the products of the CUP, in which periplasmic chaperones cooperate with outer-membrane usher proteins to polymerize fimbrin (pilin) subunits and produce these fimbrial organelles. More CUP-assembled pilus operons have been found in UPEC than in commensal bacteria, in addition to those expressing type 1 and P fimbriae. However, the receptors and activities of these extra UPEC-associated fimbriae have not been fully validated, and neither have those of type 1 and P fimbriae. S, F1C, and type 9 fimbriae are enriched in UPEC but less well conserved and provide a weaker contribution to biofilm formation than type 1 and P fimbriae. In frozen tissue sections, they have been shown to have the ability to bind to human kidney epithelia, and they may have different functions during different UTI phases. F1C fimbriae, part of the S fimbriae superfamily, are found in about 30% of UPEC strains. The adhesive virulence factor of S fimbriae has been identified in UPEC. Additionally, the binding ability of S fimbriae with sialic acid molecules has led to urosepsis. Type 9 fimbriae play a significant role in the formation of biofilms on abiotic surfaces, which may explain their contribution to CAUTIs. Like Auf, F1C, S, and type 9 fimbriae, type 3 fimbriae contribute to bacterial colonization and biofilm formation processes in UPEC. In addition, the Ygi pilus provided a slight advantage during kidney colonization, whereas the Yad pilus was found to contribute to the adhesion of UPEC to bladder epithelial cells in vitro but was not necessary for experimental UTI in mice. While fimbriae are essential in the initial attachment of UPEC to the mucosa of the urinary tract, the bacteria also produce many outer-membrane vesicles, which may be crucial in the pathophysiology of the illness. Gram-negative bacteria produce outer-membrane vesicles at all phases of their development. The creation of membrane vesicles is thought to be a “smart” technique for bacteria to protect their toxins and an effective way to transport them to the host cell. TosA, a new adhesin released by a related type 1 secretion pathway, was recently reported. About 30% of urinary tract isolates include TosA, which is expressed during UTIs. However, the function of TosA in UTIs remains unknown. FdeC, another adhesin, is allegedly produced exclusively when in contact with host cells and is well conserved across all pathotypes of E. coli and intestinal commensals. The presence of FdeC provided the mouse model with a competitive edge in bladder and kidney colonization, while the immunization of mice with FdeC antigens had no effect on bladder infection and only protected against kidney infection. UpaG, another autotransporter, promoted cell aggregation and the formation of biofilms and provided adherence to epithelial cells of the human bladder. However, UpaG may not be required for colonization. In addition, the iron-regulated adhesin Iha was demonstrated to mediate adhesion to bladder epithelial cells and grant UPEC a significant advantage in a mouse model of a UTI. An additional structure, the curli protein, is usually produced by E. coli and contributes to adhesion, host colonization, biofilm formation, and invasion. The extracellular nucleation/precipitation mechanism is included in the pathway for curli assembly on the bacterial surface, which differs from CUP and other pilus assembly systems. Through this mechanism, curli subunit proteins are first secreted onto the cell surface, before being incorporated into the growing fiber. Several studies have demonstrated that curli recognition is mediated by TLR2, which can result in the activation of pro-inflammatory molecules such as IL-6, IL-8, and TNF-α. Consistent with the above results, a study of the murine urinary tract reported that the curli shows multiple functions, including a pro-inflammatory response. In summary, although the roles of other fimbriae and non-fimbrial adhesins have been explored, P fimbriae and type 1 fimbriae play the most important role in bacterial action.

2.2. Flagella-Mediated Motility

In addition to adherence, bacterial motility is another characteristic that is usually associated with the virulence of bacterial infections. Flagella are complex surface structures that mediate motility and contribute to fitness during UPEC UTIs. The regulation of flagella and fimbriae has been shown to be coordinated. A transcriptional regulator called PapX was found to be present at the 3′ end of the P fimbrial operon in UPEC. The flagellin protein (FlaA), flagella production, and the motility of bacteria were all decreased by the overexpression of PapX. In addition, as a transcriptional repressor, PapX inhibited the transcription of the flhDC gene, which acts as a sort of master regulator of flagellar motility. Therefore, the flagella and fimbriae in E. coli are connected.

Furthermore, flagella-related gene expression was regulated during the growth phase of E. coli, indicating that flagella are involved in several functions during the processes of adhesion, maturation, and proliferation. During the processes of adhesion and colonization, a torsional change in the outer membrane of bacteria happens after contact with a urinary catheter. This kind of change can be sensed by regulators of the flagellar master operon proteins, which induce the expression of flagella to produce the highly flagellated bacteria that are required for swarming during UTIs. On the other hand, flagella participate in the formation of a multicellular bacterial community that is protected from immune responses, antimicrobial agents, and other stresses. Therefore, bacteria can mature and proliferate rapidly. Additionally, the ascent of UPEC to the upper urinary system, which reaches its peak in the murine kidney, coincided with the growth of flagella. The importance of flagella for kidney colonization has not been proven, though several mutants with decreased flagellar motility were not found to be consistently deficient during kidney colonization in competitive infection studies.

2.3. Toxins

Three main types of toxins are produced by UPEC and secreted into their surroundings: hemolysin, cytotoxic necrotizing factor 1 (CNF1), and secreted autotransporter toxins. Hemolysin, encoded by the hlyCABD operon, is a prototypical calcium-dependent repeats in toxin secreted protein that can penetrate uroepithelial cell membranes. Although hemolysin has not been shown to be necessary for colonization in experimental UTI, it does contribute to virulence because it is associated with renal damage and scarring. According to reports, it induces Ca2+ oscillations in renal tubular epithelial cells at small physiological doses, further disrupting normal urine flow, thereby enhancing UPEC ascension and colonization in the ureters and kidney parenchyma. Furthermore, hemolysin was also found to induce pro-inflammatory caspase-1/caspase-4-dependent cell death in bladder epithelial cells, resulting in cell exfoliation. In addition, hemolysin can attenuate UPEC strains during acute infections in mice, suggesting that acute bladder exfoliation is a host defense mechanism. CNF1 activity causes the Rho family of GTP-binding proteins to be constitutively activated, which induces host cells to remodel their cytoskeletons. CNF1 has been linked to host cell invasion and cellular adhesion, which might represent fitness factors in hosts. In addition, UPEC strains positively expressing CNF1 increase inflammation and bladder cell apoptosis through the activation of the Rho GTP-binding proteins Rac1, RhoA, and CDC42, suggesting that CNF1 might stimulate the exfoliation of bladder cells in vivo, thereby exposing underlying tissues. Other UPEC toxins, i.e., serine protease autotransporters of Enterobacteriaceae (SPATEs) including Sat, Pic, and Tsh, have been proven to contribute to renal pathology. Sat (secreted autotransporter toxin) mediates cytopathic effects on bladder and kidney cells in vitro and elongates kidney cells with the apparent impairment of cellular junctions. In addition, it can degrade human coagulation factor V and induce autophagic cell detachment. Pic, acting as a mucinase, is expressed during infection. However, it is unnecessary for colonization. Tsh, also called vat, (vacuolating autotransporter toxin) in CFT073, is again expressed during infection and contributes to UTIs.

2.4. Metal Acquisition

Iron, an essential nutrient, is ingested by hosts and can be acquired by bacterial pathogens. Iron acquisition is another requirement for bacterial virulence. The most diverse and broadly distributed iron acquisition mechanisms used by bacteria are siderophore acquisition systems. The primary function of siderophores, which are small chelating molecules with a very high affinity for iron, is assumed to be scavenging ferric iron (Fe3+). Deleting rhyB in CFT073 reduced siderophore production and decreased bladder and kidney colonization. A small regulatory noncoding RNA, rhyB, plays a role in the regulation of siderophore production in E. coli. Direct host iron capture occurs either from free heme or from proteins containing heme, such as hemoglobin. Heme is a direct source of iron in vivo that can be obtained via the direct heme uptake systems in UPEC. Hma and ChuA, which are iron-binding receptors, bind to heme and transport it to the periplasm. An ATP-binding cassette (ABC) transporter is then used by ChuT to mediate further transfer to the cytoplasm. ChuA is extensively expressed in IBCs, and a deletion mutant deficient in this heme transporter greatly shrinks IBCs in vivo. Additionally, microbes can sequester host iron through siderophores with high affinity, such as enterobactin, salmochelins, aerobactin, and yersiniabactin. Enterobactin is broadly conserved among E. coli strains, whereas the production of yersiniabactin, salmochelin, and aerobactin is concentrated in UPEC. Salmochelins are encoded by the iroBCDEN gene cluster. By escaping the effects of the host lipocalin-2 molecule, this siderophore increases the pathogenicity of ExPEC strains. Salmochelins exhibit greater affinity than enterobactin and are highly expressed at a low pH. IroN, the salmochelin receptor, may have numerous functions, as it has been demonstrated to facilitate the bacterial invasion of bladder epithelial cells in vitro, and a mutant UPEC strain lacking IroN was inhibited in a cystitis mouse model. Yersiniabactin, a known siderophore, also contributes to UPEC resistance to urine copper toxicity. In addition, the harmful effects of copper (II) ions are sequestered by yersiniabactin, perhaps improving resistance to phagocyte killing. Enterobactin, a highly conserved siderophore, contributes to copper sensitivity, indicating that the seeming redundancy of siderophores may be a bacterial adaptation to inhabiting different host niches.

In short, nearly all common iron-acquisition-associated genes are significantly positively selected in UPEC clinical isolates. In the urine, bladder, and kidneys of mice, the asymptomatic bacteriuria isolate UPEC 83972 outcompeted a mutant strain lacking salmochelin and enterobactin. Aerobactin appears to be crucial for bladder fitness in the pyelonephritis isolate CFT073, which does not manufacture yersiniabactin, indicating that these two siderophores may have overlapping roles. As a result, multiple bacterial iron acquisition mechanisms have been chosen for UPEC, perhaps in part because of their function in IBC formation, which may make targeting them with vaccines or therapeutics difficult. This problem might be solved by including multiple siderophore receptor antigens in a single vaccination. However, the TonB inner-membrane protein is necessary for all siderophore receptors to transmit the energy required for import. TonB deletion from a UPEC strain was reported to significantly decrease pathogenicity in the kidney and, to a lesser extent, the bladder. Therefore, discovering small molecules or medicinal plants to target TonB inhibition may be a successful anti-infection strategy.

2.5. Intracellular Bacterial Communities (IBCs)

E. coli can enter the cytoplasm after adhering to and being taken up by the host cell, where they multiply rapidly. The bacteria eventually multiply excessively over several generations and form IBCs, which are distinctive in the acute stage of infection. Additionally, dispersal from the IBC is essential for bacterial persistence. During the first 12–16 h of an experimental mouse bladder infection, an only partially understood differentiation program contributed to IBC maturation. The rapidly multiplying bacteria initially adopted a coccoid morphology, then changed back to a rod-like shape as the IBC matured, and finally fluxed away from the IBC. Then, frequently in the form of filaments, UPEC protruded from the dying urothelial cells and colonized and invaded nearby cells, initiating a second round of IBC formation (Figure 5). Experimental UPEC infection in mice did not fully recapitulate IBC development. In urine sediments from women with recurrent cystitis, IBCs have been identified through translational investigations, while evidence of IBCs was not found when the UTI pathogen was a Gram-positive organism. In addition, the IBC pathway is also used by other Gram-negative uropathogens expressing type 1 fimbriae, including Klebsiella pneumonia, Enterobacter spp., and Citrobacter freundii. These findings collectively imply that the IBC pathway is a key mechanism for the establishment of UTIs in mammalian bladders by Gram-negative uropathogens expressing type 1 fimbriae. Additionally, IBCs with biofilm-like structures are shielded from components of the host immune response, including neutrophils and antibiotics. Less differentiated cells in the lower levels of the urothelium become exposed to bacteria at the luminal surface because of the loss of superficial cells during the exfoliation process. As a result of the denser actin network in these cells, UPEC cells are not able to replicate at these sites. These aggregates of quiescent UPEC cells have been called quiescent intracellular reservoirs (QIRs). The emergence of either IBCs or QIRs contributes to the recurrence of UTIs, owing to bacteria fluxing out of infected host cells and invading new cells. In conclusion, the IBC pathway is a significant target for therapeutic intervention.

2.6. Strategies for Evading Host Defenses

The infection causes the host to have a significant pro-inflammatory reaction, which is followed by an inflow of neutrophils and attempted eradication of bacteria. Unlike commensal strains, UPEC may be able to block this induction of pro-inflammatory mediators in addition to colonizing the host and causing damage to the nearby tissue. Another strategy is escaping from immune recognition by either hiding intracellularly or masking the immunogenic surface structures.

Some fitness and virulence factors may have characteristics that shield UPEC from the host immune response. For instance, as mentioned above, iron is a crucial nutrient that UPEC must collect during infection, and the siderophore enterobactin is one route of iron acquisition. However, the neutrophil-expressed and neutrophil-released host protein lipocalin-2 specifically binds to and sequesters enterobactin, preventing it from providing UPEC with iron. Enterobactin can be modified by UPEC through glycosylation, and this modified enterobactin, called salmochelin, is not bound by the host protein lipocalin-2 and thus is not inhibited in its iron-sequestering function.

The major component of the cell wall in Gram-negative bacteria is LPS (also called endotoxin), which is highly immunogenic. The hydrophobic lipid A, core oligosaccharide, and repeats of O-antigen subunits make up the structure of LPS. The highly conserved outer leaflet of the membrane contains the hydrophobic lipid A, which mediates the toxicity of LPS. The O antigen, which is exposed at the surface of the bacteria and constitutes the major immunogen, is bound to the oligosaccharide core. Thanks to several LPS O antigens, UPEC has the capacity to dampen the induction of cytokines and chemokines in epithelial cells. The ability of UPEC strains to inhibit the induction of interleukin-6 (IL-6) and IL-8 is neutralized by the disruption of the rfa operon, particularly the deletion of waaL, which codes for the O-antigen ligase. In vivo, this process is accompanied by increased neutrophil recruitment and elimination. Additionally, serum resistance is linked to a few O antigens that are often detected in UPEC. For instance, the cystitis strains UTI89 and NU14 belong to the O18 serotype, while the pyelonephritis strains CFT073 and 536 belong to the O6 serotype. The O18 and O6 serotypes are both associated with serum resistance.

Biofilm and extracellular matrix components have also been implicated as contributors to evading host defenses. In biofilms, bacterial communities are formed and embedded in an extracellular matrix, which is mainly composed of exopolysaccharides, nucleic acids, and proteins. Bacteria within biofilms are effectively sheltered against adverse environmental conditions, including antimicrobial treatment and endogenous host immune defense. Therefore, the ability of bacteria to form a biofilm could be attributed to the combined action of adhesion, the production of an extracellular matrix, and growth characteristics. The pathogenesis of several diseases, including chronic mastitis and pyelonephritis, is associated with the formation of biofilms by bacteria. Additionally, UPEC produce more biofilms in vitro than commensal fecal isolates, proving that biofilm contributes to E. coli urovirulence. Moreover, the increasing production of exopolysaccharides and biofilms in UPEC can result in more severe and persistent infections. It is surprising that persisting UPEC isolates do not consistently produce more biofilms in vitro than isolates from sporadic infections, suggesting that in vitro biofilm formation does not necessarily reflect the in vivo situation. Generally, exopolysaccharides can promote the long-term colonization and persistence of UPEC in the urinary tract. Among them, the most noteworthy exopolysaccharides are capsular polysaccharides, poly-N-acetyl glucosamine, and cellulose. By covering highly immunogenic structures, cellulose can reduce the immune response to bacteria, and other exopolysaccharides may have similar functions.

Interestingly, the phase variation of type 1 fimbrial genes may help UPEC evade immune system recognition. A promoter on an invertible element upstream of the target genes in UPEC regulates the expression of type 1 fimbrial operons, and the orientation of the promoter is controlled by multiple recombinase enzymes. Two of these enzymes, FimB and FimE, are encoded upstream of the fimbrial operon. In addition, IpuA and IpbA, two additional recombinases, mediate the switching of the invertible element independent of FimB and FimE. In contrast to FimE and IpbA, which can only turn expression off and on, respectively, FimB and IpuA can mediate the bidirectional switching of the promoter. This process is regulated in a complex manner and is influenced by a multitude of environmental factors, such as temperature, osmolarity, pH, and oxygen levels. Furthermore, at least three regulatory proteins are also involved, including Lrp, IHF, and H-NS. When the promoters are in the ‘on’ position, the genes expressing fimbriae are transcribed, and the bacteria can be recognized by antibodies. On the contrary, bacteria with their promoters in the ‘off’ position are not recognized by these antibodies, thus essentially evading the host defense.

3. Treatment of Urinary Tract Infections

Antibiotics have been used to combat UTIs since the introduction of sulfonamides in the 1940s. Until now, antibiotics have remained the most recommended therapeutic for UTIs. However, increasing antibiotic resistance and high recurrence rates have significantly impacted the social burden of UTIs. In addition, the excessive use of antibiotics can cause long-term changes in the normal microbiota of the vagina and gastrointestinal tract and lead to liver and kidney damage, a flora imbalance, and other problems. Ideally, alternative therapies will be developed to combat the development of resistance and increase the effectiveness of antibiotics. Many promising approaches are under development, ranging from leveraging UTI pathogenesis to targeting virulence pathways. In theory, these antimicrobial therapies should be effective in reducing the ability of UTI pathogens to cause disease without causing other adverse effects. Furthermore, alternative therapies should target specific processes critical to UTI pathogenesis.

Below, we summarize the status of the use of antibiotics as traditional pharmacologic therapies and discuss the current challenges that have arisen from the emergence of multidrug-resistant bacterial strains. We emphasize the significant potential of vaccines and medicinal plants with antibacterial activity as anti-UTI medicines.

3.1. Antibiotics and Multidrug Resistance

Currently, patients with clinically symptomatic UTIs are usually treated with antibiotics. Several factors should be considered in the selection of the appropriate therapy, including host factors (such as sex, the potential for adverse effects, a compromised immune system, or urologic abnormalities), the severity of the illness (such as the duration of therapy), and the risk of multidrug resistance (such as the activity spectrum of the antimicrobial agent and resistance prevalence for the community). In addition, the management of UTIs is influenced by the increasing prevalence of resistant organisms and the potential for the spread of resistance among normal host flora with the use of broad-spectrum antibiotics.

Four agents are recommended for first-line therapy: nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), pivmecillinam, and fosfomycin tromethamine. Two alternative agents are also recommended: β-lactams and fluoroquinolones (Table 1). An important recommendation should be noted. Owing to the risk of serious harm outweighing the benefits, fluoroquinolones (for example, ciprofloxacin) have been transferred to the latter category of agents and should only be used when no other effective oral options are available. Nitrofurantoin has been an option for the management of UTIs for more than 70 years. However, nitrofurantoin does not achieve high serum concentrations and has poor tissue penetration. Therefore, it should be avoided if pyelonephritis is possible and is contraindicated in patients with renal failure. The adverse effect profile of nitrofurantoin includes nausea, headache, and gastrointestinal effects. Higher doses or longer durations of use may lead to significant hepatic and pulmonary toxicity. Nitrofurantoin affords comparable efficacy to TMP-SMX for UTIs in terms of both clinical and microbiological cures. TMP, with or without SMX, has been the mainstay therapy for UTIs for the past 40 years. It is also the first-line drug for acute UTIs and pyelonephritis. However, the main limitation of using TMP–SMX is the increasing rate of resistance among uropathogens. The efficacy of pivmecillinam for the empirical treatment of acute uncomplicated UTIs was initially reported in clinical trials published in the 1970s. Several studies have confirmed earlier reports and clinical experience suggesting that pivmecillinam is effective and well tolerated for the treatment of acute cystitis in women. Furthermore, the resistance rate of pivmecillinam is lower than that of other recommended agents and is relatively stable over time. Fosfomycin tromethamine, a soluble salt of fosfomycin, is approved for the treatment of uncomplicated UTIs in women. Although surveys show that it remains active against other antibiotic-resistant Gram-negative organisms, data supporting its efficacy for the treatment of MDR-uropathogens are limited. Given the concerns that its widespread use will increase drug resistance, it is not a popular first-line choice in the treatment of complicated UTIs. β-lactams and fluoroquinolones are second-line therapies. β-lactams show increased adverse effects compared with other choices, while the risk of fluoroquinolones may outweigh their benefits for treatment.

However, owing to the widespread emergence of antibiotic-resistance mechanisms (Figure 6), the treatment of UTIs is becoming increasingly difficult. Currently, UPEC isolated from clinics contain various types of plasmids encoding extended-spectrum β-lactamases (ESBLs), which include temoniera (TEM), sulfhydryl variables (SHVs), oxacillinases (OXAs), cefotaximases (CTX-Ms), AmpC-type β-lactamases, and carbapenemases. Originating in Klebsiella pneumoniae and Escherichia coli, ESBLs are now widespread across the family of Enterobacteriaceae. ESBLs are β-lactamases with broad activity against penicillins and cephalosporins. They are encoded by plasmids or chromosomes and function by splitting the amide bond of the β-lactam ring, thus inactivating β-lactam antibiotics. Among them, TEM and SHVs are common in Asia, and CTX-Ms are the most prevalent β-lactamases in community-associated isolates. OXAs are typically encoded by plasmids, which can hydrolyze β-lactam rings, thereby increasing the resistance of ampicillin, cephalothin, and oxacillin. AmpC enzymes, typically encoded by chromosomes, hydrolyze almost all third-generation and extended-spectrum cephalosporins and are resistant to β-lactamase inhibitors. The carbapenemase ESBLs confer resistance to carbapenems and extended-spectrum cephalosporins. These plasmids have rapidly spread resistance to third-generation cephalosporins and other antibiotics. Several studies have reported that UPEC isolates are resistant to ampicillin, oral first-generation cephalosporins, TMP-SMX, cefuroxime, cotrimoxazole, amoxicillin-clavulanate, nalidixic acid, cefradine, and aminopenicillins. Figure 7 depicts the representative antibiotic structural formulations whose resistance to UPEC has been demonstrated (orange background) and those showing susceptibility to UPEC (purple background). All in all, the troubling trend toward a high prevalence of multidrug-resistant uropathogens has stimulated the development of alternative control measures and treatment options.

In short, with the widespread use of antimicrobial drugs and the increasing number of drug-resistant strains, the “golden age” of antibiotics is waning, and fewer antibiotics are available. To minimize the above problems, antibiotic selection should be based on local sensitivity patterns and adjusted once culture results are available. Furthermore, the unnecessary treatment of asymptomatic bacteriuria should be avoided. In addition, the disturbing trend toward a high prevalence of multidrug-resistant uropathogens has stimulated the development of complementary and alternative medicines.

3.2. Preventative Strategies and Alternative Therapeutics for Urinary Tract Infections

Antibiotics will continue to be an unavoidable resource for the treatment of UTIs on a case-by-case basis. However, numerous effective strategies have been developed by bacteria to overcome therapeutic procedures and survive in the urinary system. Moreover, excessive use of antibiotics can lead to the occurrence of drug resistance and interfere with the intestinal microbiota. Therefore, it is necessary to search for preventative strategies and alternative remedies. In recent years, a plethora of potential drugs have been found to inhibit bacterial adhesion or weaken the effect of siderophores—such as vitamin D, estrogens, and probiotics. However, these drugs are still in the preclinical research stage as a means of preventing or treating UTIs. Therefore, the advantages of vaccines and medicinal plants are being considered. Medicinal plants, used in many countries as an alternative treatment for UTIs, contain a wide variety of phytochemicals and secondary metabolites, which are the most promising sources of compounds exerting antibacterial activity. Here, we summarize the most effective alternative remedies against UPEC, focusing on vaccines and medicinal plants.

3.2.1. Vaccines

The creation of vaccines to prevent UPEC UTIs is of great clinical and academic importance due to the serious consequences of these infections and the current dearth of efficient, nonantibiotic prophylactic measures. These immunizations will likely help certain patient populations. UPEC vaccination would undoubtedly be a major benefit for patients, particularly those who suffer from recurrent infections or are more likely to develop infections. The following elements should be considered when developing an effective UPEC vaccine strategy: (a) the heterogeneity of UPEC strains; (b) the production of multiple virulence factors by UPEC strains; (c) potential adverse effects on the commensal microbiota of the intestine; and (d) comprehensive and efficient drug effects for both the upper and lower urinary tract. An efficient vaccine should be able to generate a protective immune response against important virulence factors during particular phases of UTI pathogenesis, such as colonization, invasion, and the formation of IBCs. Among the steps involved in UPEC infections, adhesins, antimicrobial peptides (AMPs), and siderophores are the most likely candidates for target antigens.

In general, vaccines to prevent UPEC can be divided into two categories: whole-cell vaccines and antigen-specific vaccines (Table 2). The most effective vaccinations created to date are whole-cell vaccines. Whether attenuated or inactivated, vaccines containing intact uropathogens expose the host to a variety of virulence factors that trigger the body’s immune response, thus achieving the goal of vaccination. Solco-Urovac, a polyvalent inactivated vaccine, was developed for humans after several decades of research in animals. It consists of ten distinct strains of heat-inactivated bacteria: six from UPEC and one strain each from Enterococcus faecalis, Proteus mirabilis, Morganella morganii, and Klebsiella pneumoniae. The vaccine was reported to protect Europeans from recurrent UTIs in a clinical trial. However, it produced significant adverse effects, such as nausea, fever, burning, bleeding, and vaginal itching, which might have led to its abandonment. StroVac, currently available for use in humans, is another intramuscular polyvalent inactivated UTI vaccine that comprises the same ten UPEC strains in a different formulation and produces few side effects in the nonantibiotic prophylaxis of recurrent UTIs. Another oral inactivated UTI vaccine, Uro-vaxom, comprises membrane proteins of 18 UPEC strains. It can protect women from recurrent UTIs, has few side effects, and has been approved for use in Europe since 1994. However, its major drawback is poor patient compliance because it requires repeated injections every three months, which limits its promotion. Other inactivated vaccines against UTIs include Urvakol, Urostim, ExPEC9V, and CP923, which promote immunogenicity in animals but have not completed clinical trials. NU14 ∆waal, the representative attenuated vaccine for UPEC, is a whole-cell vaccine. It was identified from a mutant of the UPEC strain NU14 that lacks the O-antigen ligase waal. In a murine UTI model, NU14 ∆waal was considerably less virulent and more inflammatory than wild-type NU14. When challenged with infection by NU14, CFT073, and four other UPEC isolates, mice were protected from infection by vaccination with NU14 ∆waal. However, the potential of NU14 ∆waal was diminished by the discovery that serial infections with NU14 ∆waal cause chronic bladder pain.

In addition, antigen-specific vaccines have been investigated as potential prevention targets, including capsular- or LPS-based, fimbrial, and non-fimbrial adhesin, iron-scavenger-receptor-based, and toxin-based vaccines. ExPEC4V, a polysaccharide-based vaccine containing the O antigens of four E. coli serotypes (O1A, O2, O6A, and O25B), induced significant IgG responses and significantly reduced the incidence of UTIs caused by UPEC even with higher bacterial doses compared with the placebo group in phase II clinical trial. Adhesins that promote the UPEC colonization of the bladder epithelium also cause host immune reactions. Therefore, adhesins can be used to create a desirable antigen candidate that can prevent adhesin-host cell-receptor interaction and obstruct the bacterial colonization of the host. In animal models, the FimH adhesin from type 1 fimbriae played a crucial role in the pathogenesis of UPEC in the lower urinary tract. It has proven to be highly efficient in treating mice when challenged with bacteria cultured under conditions that induce type 1 fimbriae. FimH can be purified either in its mannose-binding native form or attached to its periplasmic chaperone FimC (FimCH). In a mouse model, both antigens were effective at preventing the colonization of various UPEC strains. Numerous preclinical investigations have demonstrated the effectiveness of FimH vaccinations in triggering an immune response and preventing UPEC. Both approaches were reported to be effective at preventing cystitis when a recombinant FimH vaccine was administered to mice either intranasally or intramuscularly. Another report showed that the subcutaneous administration of recombinant FimH coupled to the flagellin subunit FliC, a TLR5 agonist and potential adjuvant, shielded mice from cystitis when challenged with a type 1 pilus-expressing clinical strain. Additionally, in murine and primate models, a FimH vaccination with alum and MF59 adjuvants or with FliC and Montanide ISA 206 adjuvants induced an immune response to UPEC and inhibited colonization. Last, a team created a FimH plasmid construct with mammalian codon optimization for use in a DNA vaccine, allowing for the induction of a protective immune response in mice when plasmid DNA was injected. Mice that received the DNA vaccination through footpad injection presented much less extensive bladder colonization and significantly higher urine IgA titers. However, most of these vaccines were later rejected due to the lack of efficacy in humans after FimH vaccination tests in clinical trials. The failure of the FimH-based vaccination was due to several factors. UPEC strains are not consistently detected by the immune system due to the variable expression of type 1 fimbriae in animal and human models. In addition, antigens developed against the fimbriae do not target their mannose-binding region. Multiple studies utilizing a range of target antigens in animal urinary tract models may be necessary to develop an efficient UTI vaccine. A TLR ligand-based vaccine using FimH adhesin is currently being explored, with the fusion of FimH adhesin to the flagellin of UPEC as a TLR5 ligand able to elicit an immune response and shield mice from UTIs. A study reported that cynomolgus monkeys receiving the FimCH vaccination intramuscularly were shielded from pyuria and bacteriuria. In addition, in mouse and primate models, the FimCH vaccine with Freund’s adjuvant induced an immune response against UPEC and inhibited colonization. However, the development of the FimCH vaccine was abandoned during phase II trials despite its safety being confirmed in phase I studies. Evidently, whether a vaccine is composed of truncated FimH or a complex of FimH with the chaperone FimC, it will eventually be rejected due to a lack of efficacy or adverse reactions in clinical trials. Moreover, the PapG adhesin from P fimbriae also plays an important role in UPEC pathogenesis. Analogous to the FimH and FimCH vaccines, a vaccine composed of truncated PapG or a complex of PapG with the chaperone PapD (PapDG) was able to protect cynomolgus monkeys from pyelonephritis. In addition, PapDG vaccines with Freund’s adjuvants were also shown to generate immune responses and reduce UPEC colonization in a mouse model.

The use of siderophore–protein conjugates was found to induce immune responses targeted at bacterial siderophores and to successfully protect against UTIs, meaning that E. coli iron acquisition systems have the same potential as UPEC vaccine candidates. IroN, IutA, IreA, and FyuA increased protection in the urinary tracts of mice in a study using an attenuated Salmonella vaccine delivery system to assess the efficacy of a multi-epitope vaccine comprising siderophore receptors. In a mouse model, researchers discovered that systemic vaccination with the salmochelin receptor IroN or IroN with Freund’s adjuvant could offer protection against UTIs, while the aerobactin receptor IutA conjugated with cholera toxin also produced potent immune responses and provided defense against UPEC infection. The intranasal administration of the yersiniabactin receptor FyuA prevented mice from contracting pyelonephritis after exposure to UPEC strain 536, which expresses FyuA. FyuA also produced potent immune responses and provided defense against UPEC infection in mouse models when used with alum as an adjuvant. Additionally, the potential antigen Hma, a heme receptor, exhibited kidney protection against challenge infection. In a similar vein, UTI symptoms were reduced in murine experimental infection models by a toxin-based vaccine including antigens such as hemolysin HlyA, recombinant hemolysin, and mutant CNF1 and HlyA toxins. As potential vaccine targets, autotransporter toxins such as FdeC from UPEC strains have also been studied. Identifying whether these results extend to human UTI patients should undoubtedly be a future study objective.

3.2.2. Medicinal Plants for the Management and Treatment of Urinary Tract Infections

With the increasing prevalence of UTIs and the economic burden for both patients and governments, developing effective anti-UTI drugs that can be quickly applied in clinical settings is important. Vaccines and small molecule formulations may be a promising option; however, the high cost (over one billion USD) and lengthy process of developing new antibacterial agents (more than 10 years) must be taken into consideration. Therefore, medicinal plants have attracted increasing interest within the scientific community. In fact, research on medicinal plants has grown significantly since the beginning of the 21st century, touching on their effectiveness in treating and preventing UTIs, their therapeutic material basis, and their mechanisms of action.

The superiority of medicinal plants has also attracted increasing research interest. As plant extracts contain a variety of phytochemicals that act against different molecular targets within bacterial cells, bacteria are less likely to develop resistance to medicinal plants, and thus they can maintain increased efficacy and decreased side effects. Medicinal plants contain a wide variety of phytochemicals and secondary metabolites and are classified according to their chemical composition, including alkaloids, coumarins, flavonoids, lectins, polypeptides, quinones, tannins, and terpenoids. The parts of the plant used to treat UTIs vary substantially, as do the chemical compositions of these parts. In addition, the plant extraction and processing methods also impact the chemical composition. Generally, the plant part, form, and dosage depend on information gathered from folk medicine or the experience of ethnophysicians. Therefore, fully developing and applying medicinal plants is a significant challenge.

Although the exact mechanisms by which plants offer curative or preventative effects against UTIs are unclear, substantial research is ongoing in this field. Studies have shown that many medicinal plants exert antibacterial activity against a variety of bacterial pathogens, and combined use with antibiotics can enhance bactericidal and bacteriostatic effects. In some cases, medicinal plants can even reverse antibiotic resistance. In addition to bactericidal and bacteriostatic effects, medicinal plants have been reported to present other mechanisms, such as antiadhesive activity, the inhibition of bacterial growth, anti-biofilm-formation activity, the inhibition of motility, the protection of host urinary cells, and the enhancement of antibacterial immunity. In Table 3, we summarize recently studied plants that achieved positive results against UPEC. We hope that this will help in the selection of clinical anti-UPEC drugs.

4. Conclusion and Future Prospects

In this review, we described an interaction network comprising UPEC, the host, and antibiotics. Vaccines and medicinal plants were also included as preventative strategies and alternative therapeutic methods for UPEC. The main pathogen of UTIs is UPEC, which can survive within the urinary tract and cause infection through a wide range of virulence factors, including fimbrial and non-fimbrial adhesins, flagella, toxins, lipopolysaccharides, surface vesicles, polysaccharide capsules, and the iron acquisition system. Hence, as vital organs, the urethra, bladder, and kidneys are often attacked by UPEC. The pathogenesis of a UTI starts with the contamination and colonization of the urethral area with UPEC. The bladder epithelium is then invaded by UPEC. Finally, UPEC release toxins that damage host tissues, resulting in upper UTIs. Severe cases can also result in life-threatening illnesses, such as bacteremia, septicemia, and urosepsis. Since the 1940s, when sulfonamides were first introduced, various antibiotics have been employed to treat UTIs and then UPEC. Until now, antibiotics have remained the most frequently recommended treatment for UTIs. However, as new and more severe diseases have emerged, the growing resistance to antibiotics has led to the recurrence and chronicity of infection, making treatment challenging and complicated.

Therefore, the highest priority in UTI research should be the development of new, effective alternative therapies, as these therapies have the potential to significantly improve the quality of life for millions of humans and reduce the overall use of antibiotics. However, the promotion of vaccines faces numerous obstacles. The notion that any novel vaccine or therapy by itself can entirely eradicate recurrent UTIs in all patients is doubtful due to the substantial contribution of the host to recurrent UTIs unless the vaccine/therapy is also able to alter the innate mucosal-immune response to uropathogens. In the urogenital niche of hosts, UPEC can predominate in the absence of immunization, but after vaccination, other uropathogens may take the position of UPEC. Furthermore, the process of developing new vaccines for the market is relatively lengthy and expensive.

Thus, a new, more efficacious, and cost-effective strategy should be developed to combat UTIs caused by UPEC. Some of the most promising sources of compounds that exert antibacterial activity against UPEC are medicinal plants. Plants have been used extensively to treat and prevent diseases for a long time. The development of reliable and efficient plant-based medicinal treatments would undoubtedly necessitate a complete understanding of the mechanisms through which medicinal plants affect UPEC and the human body. An overview of the antibacterial activities of medicinal plants that work against UPEC was provided in this review. However, to completely understand how these plants prevent or treat UTIs caused by UPEC, more research is required.

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    Not in our library10.1073/pnas.0600938103

  29. 29.

    Behzadi P. Classical chaperone-usher (CU) adhesive fimbriome: Uropathogenic Escherichia coli (UPEC) and urinary tract infections (UTIs). Folia Microbiol. 2020;65:45-65.

    Not in our library10.1007/s12223-019-00719-x

  30. 30.
    Molecular analysis of type 3 fimbrial genes from <it>Escherichia coli</it>, <it>Klebsiella </it>and <it>Citrobacter </it>species · 2010
    Not checked
  31. 31.

    Zavialov A., Zav’yalova G., Korpela T., Zav’yalov V. FGL chaperone-assembled fimbrial polyadhesins: Anti-immune armament of Gram-negative bacterial pathogens. FEMS Microbiol. Rev. 2007;31:478-514.

    Not in our library10.1111/j.1574-6976.2007.00075.x

  32. 32.

    Zhou G., Mo W.J., Sebbel P., Min G., Neubert T.A., Glockshuber R., Wu X.R., Sun T.T., Kong X.P. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: Evidence from in vitro FimH binding. J. Cell Sci. 2001;114:4095-4103.

    Not in our library10.1242/jcs.114.22.4095

  33. 33.
    Integrin-Mediated Host Cell Invasion by Type 1–Piliated Uropathogenic Escherichia coli · 2007
    No notice
  34. 34.

    Mossman K.L., Mian M.F., Lauzon N.M., Gyles C.L., Lichty B., Mackenzie R., Gill N., Ashkar A.A. Cutting edge: FimH adhesin of type 1 fimbriae is a novel TLR4 ligand. J. Immunol. 2008;181:6702-6706.

    Not in our library10.4049/jimmunol.181.10.6702

  35. 35.

    Behzadi E., Behzadi P. The role of toll-like receptors (TLRs) in urinary tract infections (UTIs). Cent. Eur. J. Urol. 2016;69:404-410.

    Not in our library10.5173/ceju.2016.871

  36. 36.

    Spaulding C.N., Klein R.D., Ruer S., Kau A.L., Schreiber H.L., Cusumano Z.T., Dodson K.W., Pinkner J.S., Fremont D.H., Janetka J.W., et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature. 2017;546:528-532.

    Not in our library10.1038/nature22972

  37. 37.

    Lund B., Lindberg F., Marklund B.I., Normark S. The PapG protein is the alpha-D-galactopyranosyl-(1----4)-beta-D-galactopyranose-binding adhesin of uropathogenic Escherichia coli. Proc. Natl. Acad. Sci. USA. 1987;84:5898-5902.

    Not in our library10.1073/pnas.84.16.5898

  38. 38.

    Klemm P., Hancock V., Schembri M.A. Fimbrial adhesins from extraintestinal Escherichia coli. Environ. Microbiol. Rep. 2010;2:628-640.

    Not in our library10.1111/j.1758-2229.2010.00166.x

  39. 39.

    Langermann S., Möllby R., Burlein J.E., Palaszynski S.R., Auguste C.G., DeFusco A., Strouse R., Schenerman M.A., Hultgren S.J., Pinkner J.S., et al. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis. 2000;181:774-778.

    Not in our library10.1086/315258

  40. 40.

    Wright K.J., Seed P.C., Hultgren S.J. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol. 2007;9:2230-2241.

    Not in our library10.1111/j.1462-5822.2007.00952.x

  41. 41.

    Schaeffer A.J. Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection. J. Urol. 2003;170:335.

    Not in our library10.1016/s0022-5347(05)63509-4

  42. 42.

    Martinez J.J., Mulvey M.A., Schilling J.D., Pinkner J.S., Hultgren S.J. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J. 2000;19:2803-2812.

    Not in our library10.1093/emboj/19.12.2803

  43. 43.

    Wright K.J., Hultgren S.J. Sticky fibers and uropathogenesis: Bacterial adhesins in the urinary tract. Future Microbiol. 2006;1:75-87.

    Not in our library10.2217/17460913.1.1.75

  44. 44.

    Sarowar S., Hu O.J., Werneburg G.T., Thanassi D.G., Li H. The Escherichia coli P and Type 1 Pilus Assembly Chaperones PapD and FimC Are Monomeric in Solution. J. Bacteriol. 2016;198:2360-2369.

    Not in our library10.1128/jb.00366-16

  45. 45.

    Saldaña Z., De la Cruz M.A., Carrillo-Casas E.M., Durán L., Zhang Y., Hernández-Castro R., Puente J.L., Daaka Y., Girón J.A. Production of the Escherichia coli common pilus by uropathogenic E. coli is associated with adherence to HeLa and HTB-4 cells and invasion of mouse bladder urothelium. PLoS ONE. 2014;9:e101200.

    Not in our library10.1371/journal.pone.0101200

  46. 46.

    Sidaway P. Infection: Exposure to human urine decreases type 1 pili expression in uropathogenic Escherichia coli. Nat. Rev. Urol. 2015;12:422.

    Not in our library10.1038/nrurol.2015.172

  47. 47.

    Greene S.E., Hibbing M.E., Janetka J., Chen S.L., Hultgren S.J. Human Urine Decreases Function and Expression of Type 1 Pili in Uropathogenic Escherichia coli. mBio. 2015;6:e00820.

    Not in our library10.1128/mbio.00820-15

  48. 48.

    Zav’yalov V., Zavialov A., Zav’yalova G., Korpela T. Adhesive organelles of Gram-negative pathogens assembled with the classical chaperone/usher machinery: Structure and function from a clinical standpoint. FEMS Microbiol. Rev. 2010;34:317-378.

    Not in our library10.1111/j.1574-6976.2009.00201.x

  49. 49.

    Conover M.S., Ruer S., Taganna J., Kalas V., De Greve H., Pinkner J.S., Dodson K.W., Remaut H., Hultgren S.J. Inflammation-Induced Adhesin-Receptor Interaction Provides a Fitness Advantage to Uropathogenic, E. coli during Chronic Infection. Cell Host Microbe. 2016;20:482-492.

    Not in our library10.1016/j.chom.2016.08.013

  50. 50.

    Chahales P., Thanassi D.G. Structure, Function, and Assembly of Adhesive Organelles by Uropathogenic Bacteria. Microbiol. Spectr. 2015;3:277-329.

    Not in our library10.1128/microbiolspec.uti-0018-2013

  51. 51.
    Bacteria-Induced Uroplakin Signaling Mediates Bladder Response to Infection · 2009
    No notice
  52. 52.

    Wang H., Min G., Glockshuber R., Sun T.T., Kong X.P. Uropathogenic, E. coli adhesin-induced host cell receptor conformational changes: Implications in transmembrane signaling transduction. J. Mol. Biol. 2009;392:352-361.

    Not in our library10.1016/j.jmb.2009.06.077

  53. 53.

    Eto D.S., Gordon H.B., Dhakal B.K., Jones T.A., Mulvey M.A. Clathrin, AP-2, and the NPXY-binding subset of alternate endocytic adaptors facilitate FimH-mediated bacterial invasion of host cells. Cell Microbiol. 2008;10:2553-2567.

    Not in our library10.1111/j.1462-5822.2008.01229.x

  54. 54.

    Schembri M.A., Sokurenko E.V., Klemm P. Functional flexibility of the FimH adhesin: Insights from a random mutant library. Infect. Immun. 2000;68:2638-2646.

    Not in our library10.1128/iai.68.5.2638-2646.2000

  55. 55.

    Sokurenko E.V., Courtney H.S., Maslow J., Siitonen A., Hasty D.L. Quantitative differences in adhesiveness of type 1 fimbriated Escherichia coli due to structural differences in fimH genes. J. Bacteriol. 1995;177:3680-3686.

    Not in our library10.1128/jb.177.13.3680-3686.1995

  56. 56.

    Chen S.L., Hung C.S., Pinkner J.S., Walker J.N., Cusumano C.K., Li Z., Bouckaert J., Gordon J.I., Hultgren S.J. Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding. Proc. Natl. Acad. Sci. USA. 2009;106:22439-22444.

    Not in our library10.1073/pnas.0902179106

  57. 57.

    Biggel M., Xavier B.B., Johnson J.R., Nielsen K.L., Frimodt-Møller N., Matheeussen V., Goossens H., Moons P., Van Puyvelde S. Horizontally acquired papGII-containing pathogenicity islands underlie the emergence of invasive uropathogenic Escherichia coli lineages. Nat. Commun. 2020;11:5968.

    Not in our library10.1038/s41467-020-19714-9

  58. 58.

    Bessaiah H., Pokharel P., Loucif H., Kulbay M., Sasseville C., Habouria H., Houle S., Bernier J., Massé É., Van Grevenynghe J., et al. The RyfA small RNA regulates oxidative and osmotic stress responses and virulence in uropathogenic Escherichia coli. PLoS Pathog. 2021;17:e1009617.

    Not in our library10.1371/journal.ppat.1009617

  59. 59.

    Roberts K.B. Urinary tract infection: Clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128:595-610.

    Not in our library10.1542/peds.2011-1330

  60. 60.

    Norinder B.S., Köves B., Yadav M., Brauner A., Svanborg C. Do Escherichia coli strains causing acute cystitis have a distinct virulence repertoire? Microb. Pathog. 2012;52:10-16.

    Not in our library10.1016/j.micpath.2011.08.005

  61. 61.

    O’Brien V.P., Hannan T.J., Schaeffer A.J., Hultgren S.J. Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr. Opin. Infect. Dis. 2015;28:97-105.

    Not in our library10.1097/qco.0000000000000130

  62. 62.

    Ishitoya S., Yamamoto S., Mitsumori K., Ogawa O., Terai A. Non-secretor status is associated with female acute uncomplicated pyelonephritis. BJU Int. 2002;89:851-854.

    Not in our library10.1046/j.1464-410x.2002.02782.x

  63. 63.

    Sauer F.G., Mulvey M.A., Schilling J.D., Martinez J.J., Hultgren S.J. Bacterial pili: Molecular mechanisms of pathogenesis. Curr. Opin. Microbiol. 2000;3:65-72.

    Not in our library10.1016/s1369-5274(99)00053-3

  64. 64.

    La Combe B., Clermont O., Messika J., Eveillard M., Kouatchet A., Lasocki S., Corvec S., Lakhal K., Billard-Pomares T., Fernandes R., et al. Pneumonia-Specific Escherichia coli with Distinct Phylogenetic and Virulence Profiles, France, 2012–2014. Emerg. Infect. Dis. 2019;25:710-718.

    Not in our library10.3201/eid2504.180944

  65. 65.

    Werneburg G.T., Thanassi D.G. Pili Assembled by the Chaperone/Usher Pathway in Escherichia coli and Salmonella. EcoSal Plus. 2018;8:1-56.

    Not in our library10.1128/ecosalplus.esp-0007-2017

  66. 66.

    Lane M.C., Mobley H.L. Role of P-fimbrial-mediated adherence in pyelonephritis and persistence of uropathogenic Escherichia coli (UPEC) in the mammalian kidney. Kidney Int. 2007;72:19-25.

    Not in our library10.1038/sj.ki.5002230

  67. 67.

    Mobley H.L., Jarvis K.G., Elwood J.P., Whittle D.I., Lockatell C.V., Russell R.G., Johnson D.E., Donnenberg M.S., Warren J.W. Isogenic P-fimbrial deletion mutants of pyelonephritogenic Escherichia coli: The role of alpha Gal(1-4) beta Gal binding in virulence of a wild-type strain. Mol. Microbiol. 1993;10:143-155.

    Not in our library10.1111/j.1365-2958.1993.tb00911.x

  68. 68.

    Elliott S.P., Yu M., Xu H., Haslam D.B. Forssman synthetase expression results in diminished shiga toxin susceptibility: A role for glycolipids in determining host-microbe interactions. Infect. Immun. 2003;71:6543-6552.

    Not in our library10.1128/iai.71.11.6543-6552.2003

  69. 69.
    Uropathogenic Escherichia coli P and Type 1 Fimbriae Act in Synergy in a Living Host to Facilitate Renal Colonization Leading to Nephron Obstruction · 2011
    No notice
  70. 70.

    Bäckhed F., Alsén B., Roche N., Angström J., von Euler A., Breimer M.E., Westerlund-Wikström B., Teneberg S., Richter-Dahlfors A. Identification of target tissue glycosphingolipid receptors for uropathogenic, F1C-fimbriated Escherichia coli and its role in mucosal inflammation. J. Biol. Chem. 2002;277:18198-18205.

    Not in our library10.1074/jbc.m111640200

  71. 71.

    Selvarangan R., Goluszko P., Singhal J., Carnoy C., Moseley S., Hudson B., Nowicki S., Nowicki B. Interaction of Dr adhesin with collagen type IV is a critical step in Escherichia coli renal persistence. Infect. Immun. 2004;72:4827-4835.

    Not in our library10.1128/iai.72.8.4827-4835.2004

  72. 72.

    Qin X., Hu F., Wu S., Ye X., Zhu D., Zhang Y., Wang M. Comparison of adhesin genes and antimicrobial susceptibilities between uropathogenic and intestinal commensal Escherichia coli strains. PLoS ONE. 2013;8:e61169.

    Not in our library10.1371/journal.pone.0061169

  73. 73.

    Subashchandrabose S., Mobley H.L.T. Virulence and Fitness Determinants of Uropathogenic Escherichia coli. Microbiol. Spectr. 2015;3:235-261.

    Not in our library10.1128/microbiolspec.uti-0015-2012

  74. 74.

    Wurpel D.J., Totsika M., Allsopp L.P., Hartley-Tassell L.E., Day C.J., Peters K.M., Sarkar S., Ulett G.C., Yang J., Tiralongo J., et al. F9 fimbriae of uropathogenic Escherichia coli are expressed at low temperature and recognise Galβ1-3GlcNAc-containing glycans. PLoS ONE. 2014;9:e93177.

    Not in our library10.1371/journal.pone.0093177

  75. 75.

    Spurbeck R.R., Stapleton A.E., Johnson J.R., Walk S.T., Hooton T.M., Mobley H.L. Fimbrial profiles predict virulence of uropathogenic Escherichia coli strains: Contribution of ygi and yad fimbriae. Infect. Immun. 2011;79:4753-4763.

    Not in our library10.1128/iai.05621-11

  76. 76.

    Ellis T.N., Kuehn M.J. Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol. Mol. Biol. Rev. 2010;74:81-94.

    Not in our library10.1128/mmbr.00031-09

  77. 77.

    Wiles T.J., Kulesus R.R., Mulvey M.A. Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp. Mol. Pathol. 2008;85:11-19.

    Not in our library10.1016/j.yexmp.2008.03.007

  78. 78.

    Vigil P.D., Alteri C.J., Mobley H.L. Identification of in vivo-induced antigens including an RTX family exoprotein required for uropathogenic Escherichia coli virulence. Infect. Immun. 2011;79:2335-2344.

    Not in our library10.1128/iai.00110-11

  79. 79.

    Vigil P.D., Stapleton A.E., Johnson J.R., Hooton T.M., Hodges A.P., He Y., Mobley H.L. Presence of putative repeat-in-toxin gene tosA in Escherichia coli predicts successful colonization of the urinary tract. mBio. 2011;2:e00066-11.

    Not in our library10.1128/mbio.00066-11

  80. 80.

    Engstrom M.D., Alteri C.J., Mobley H.L. A conserved PapB family member, TosR, regulates expression of the uropathogenic Escherichia coli RTX nonfimbrial adhesin TosA while conserved LuxR family members TosE and TosF suppress motility. Infect. Immun. 2014;82:3644-3656.

    Not in our library10.1128/iai.01608-14

  81. 81.
    FdeC, a Novel Broadly Conserved <named-content content-type="genus-species">Escherichia coli</named-content> Adhesin Eliciting Protection against Urinary Tract Infections · 2012
    Not checked
  82. 82.

    Valle J., Mabbett A.N., Ulett G.C., Toledo-Arana A., Wecker K., Totsika M., Schembri M.A., Ghigo J.M., Beloin C. UpaG, a new member of the trimeric autotransporter family of adhesins in uropathogenic Escherichia coli. J. Bacteriol. 2008;190:4147-4161.

    Not in our library10.1128/jb.00122-08

  83. 83.

    Johnson J.R., Jelacic S., Schoening L.M., Clabots C., Shaikh N., Mobley H.L., Tarr P.I. The IrgA homologue adhesin Iha is an Escherichia coli virulence factor in murine urinary tract infection. Infect. Immun. 2005;73:965-971.

    Not in our library10.1128/iai.73.2.965-971.2005

  84. 84.

    Barnhart M.M., Chapman M.R. Curli biogenesis and function. Annu. Rev. Microbiol. 2006;60:131-147.

    Not in our library10.1146/annurev.micro.60.080805.142106

  85. 85.

    Kim S.M., Lee H.W., Choi Y.W., Kim S.H., Lee J.C., Lee Y.C., Seol S.Y., Cho D.T., Kim J. Involvement of curli fimbriae in the biofilm formation of Enterobacter cloacae. J. Microbiol. 2012;50:175-178.

    Not in our library10.1007/s12275-012-2044-2

  86. 86.

    Nicastro L.K., de Anda J., Jain N., Grando K.C.M., Miller A.L., Bessho S., Gallucci S., Wong G.C.L., Tükel Ç. Assembly of ordered DNA-curli fibril complexes during Salmonella biofilm formation correlates with strengths of the type I interferon and autoimmune responses. PLoS Pathog. 2022;18:e1010742.

    Not in our library10.1371/journal.ppat.1010742

  87. 87.

    Tükel C., Raffatellu M., Humphries A.D., Wilson R.P., Andrews-Polymenis H.L., Gull T., Figueiredo J.F., Wong M.H., Michelsen K.S., Akçelik M., et al. CsgA is a pathogen-associated molecular pattern of Salmonella enterica serotype Typhimurium that is recognized by Toll-like receptor 2. Mol. Microbiol. 2005;58:289-304.

    Not in our library10.1111/j.1365-2958.2005.04825.x

  88. 88.

    Bian Z., Brauner A., Li Y., Normark S. Expression of and cytokine activation by Escherichia coli curli fibers in human sepsis. J. Infect. Dis. 2000;181:602-612.

    Not in our library10.1086/315233

  89. 89.
    Uropathogenic Escherichia coli Modulates Immune Responses and Its Curli Fimbriae Interact with the Antimicrobial Peptide LL-37 · 2010
    No notice
  90. 90.

    Lane M.C., Lockatell V., Monterosso G., Lamphier D., Weinert J., Hebel J.R., Johnson D.E., Mobley H.L. Role of motility in the colonization of uropathogenic Escherichia coli in the urinary tract. Infect. Immun. 2005;73:7644-7656.

    Not in our library10.1128/iai.73.11.7644-7656.2005

  91. 91.

    Wright K.J., Seed P.C., Hultgren S.J. Uropathogenic Escherichia coli flagella aid in efficient urinary tract colonization. Infect. Immun. 2005;73:7657-7668.

    Not in our library10.1128/iai.73.11.7657-7668.2005

  92. 92.

    Simms A.N., Mobley H.L. PapX, a P fimbrial operon-encoded inhibitor of motility in uropathogenic Escherichia coli. Infect. Immun. 2008;76:4833-4841.

    Not in our library10.1128/iai.00630-08

  93. 93.

    Girón J.A., Torres A.G., Freer E., Kaper J.B. The flagella of enteropathogenic Escherichia coli mediate adherence to epithelial cells. Mol. Microbiol. 2002;44:361-379.

    Not in our library10.1046/j.1365-2958.2002.02899.x

  94. 94.

    Nakamura Y., Yamamoto N., Kino Y., Yamamoto N., Kamei S., Mori H., Kurokawa K., Nakashima N. Establishment of a multi-species biofilm model and metatranscriptomic analysis of biofilm and planktonic cell communities. Appl. Microbiol. Biotechnol. 2016;100:7263-7279.

    Not in our library10.1007/s00253-016-7532-6

  95. 95.

    Lane M.C., Alteri C.J., Smith S.N., Mobley H.L. Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract. Proc. Natl. Acad. Sci. USA. 2007;104:16669-16674.

    Not in our library10.1073/pnas.0607898104

  96. 96.

    Rosen D.A., Pinkner J.S., Jones J.M., Walker J.N., Clegg S., Hultgren S.J. Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect. Immun. 2008;76:3337-3345.

    Not in our library10.1128/iai.00090-08

  97. 97.

    Uhlén P., Laestadius A., Jahnukainen T., Söderblom T., Bäckhed F., Celsi G., Brismar H., Normark S., Aperia A., Richter-Dahlfors A. Alpha-haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells. Nature. 2000;405:694-697.

    Not in our library10.1038/35015091

  98. 98.

    Nagamatsu K., Hannan T.J., Guest R.L., Kostakioti M., Hadjifrangiskou M., Binkley J., Dodson K., Raivio T.L., Hultgren S.J. Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc. Natl. Acad. Sci. USA. 2015;112:E871-E880.

    Not in our library10.1073/pnas.1500374112

  99. 99.

    Lemonnier M., Landraud L., Lemichez E. Rho GTPase-activating bacterial toxins: From bacterial virulence regulation to eukaryotic cell biology. FEMS Microbiol. Rev. 2007;31:515-534.

    Not in our library10.1111/j.1574-6976.2007.00078.x

  100. 100.

    Petracchini S., Hamaoui D., Doye A., Asnacios A., Fage F., Vitiello E., Balland M., Janel S., Lafont F., Gupta M., et al. Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division. Nat. Commun. 2022;13:6059.

    Not in our library10.1038/s41467-022-33803-x

  101. 101.

    Hofman P., Le Negrate G., Mograbi B., Hofman V., Brest P., Alliana-Schmid A., Flatau G., Boquet P., Rossi B. Escherichia coli cytotoxic necrotizing factor-1 (CNF-1) increases the adherence to epithelia and the oxidative burst of human polymorphonuclear leukocytes but decreases bacteria phagocytosis. J. Leukoc. Biol. 2000;68:522-528.

    Not in our library10.1189/jlb.68.4.522

  102. 102.
    The Diversity of Escherichia coli Pathotypes and Vaccination Strategies against This Versatile Bacterial Pathogen · 2023
    No notice
  103. 103.

    Heimer S.R., Rasko D.A., Lockatell C.V., Johnson D.E., Mobley H.L. Autotransporter genes pic and tsh are associated with Escherichia coli strains that cause acute pyelonephritis and are expressed during urinary tract infection. Infect. Immun. 2004;72:593-597.

    Not in our library10.1128/iai.72.1.593-597.2004

  104. 104.

    Guyer D.M., Radulovic S., Jones F.E., Mobley H.L. Sat, the secreted autotransporter toxin of uropathogenic Escherichia coli, is a vacuolating cytotoxin for bladder and kidney epithelial cells. Infect. Immun. 2002;70:4539-4546.

    Not in our library10.1128/iai.70.8.4539-4546.2002

  105. 105.

    Guyer D.M., Henderson I.R., Nataro J.P., Mobley H.L. Identification of sat, an autotransporter toxin produced by uropathogenic Escherichia coli. Mol. Microbiol. 2000;38:53-66.

    Not in our library10.1046/j.1365-2958.2000.02110.x

  106. 106.

    Dutta P.R., Cappello R., Navarro-García F., Nataro J.P. Functional comparison of serine protease autotransporters of enterobacteriaceae. Infect. Immun. 2002;70:7105-7113.

    Not in our library10.1128/iai.70.12.7105-7113.2002

  107. 107.

    Liévin-Le Moal V., Comenge Y., Ruby V., Amsellem R., Nicolas V., Servin A.L. Secreted autotransporter toxin (Sat) triggers autophagy in epithelial cells that relies on cell detachment. Cell Microbiol. 2011;13:992-1013.

    Not in our library10.1111/j.1462-5822.2011.01595.x

  108. 108.

    Parham N.J., Srinivasan U., Desvaux M., Foxman B., Marrs C.F., Henderson I.R. PicU, a second serine protease autotransporter of uropathogenic Escherichia coli. FEMS Microbiol. Lett. 2004;230:73-83.

    Not in our library10.1016/s0378-1097(03)00862-0

  109. 109.

    Nichols K.B., Totsika M., Moriel D.G., Lo A.W., Yang J., Wurpel D.J., Rossiter A.E., Strugnell R.A., Henderson I.R., Ulett G.C., et al. Molecular Characterization of the Vacuolating Autotransporter Toxin in Uropathogenic Escherichia coli. J. Bacteriol. 2016;198:1487-1498.

    Not in our library10.1128/jb.00791-15

  110. 110.
    The Vacuolating Autotransporter Toxin (Vat) of Escherichia coli Causes Cell Cytoskeleton Changes and Produces Non-lysosomal Vacuole Formation in Bladder Epithelial Cells · 2020
    Not checked
  111. 111.
    The Battle for Iron between Bacterial Pathogens and Their Vertebrate Hosts · 2010
    No notice
  112. 112.

    Valdebenito M., Bister B., Reissbrodt R., Hantke K., Winkelmann G. The detection of salmochelin and yersiniabactin in uropathogenic Escherichia coli strains by a novel hydrolysis-fluorescence-detection (HFD) method. Int. J. Med. Microbiol. 2005;295:99-107.

    Not in our library10.1016/j.ijmm.2005.02.001

  113. 113.

    Jones R.L., Peterson C.M., Grady R.W., Cerami A. Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth. J. Exp. Med. 1980;151:418-428.

    Not in our library10.1084/jem.151.2.418

  114. 114.

    Porcheron G., Habib R., Houle S., Caza M., Lépine F., Daigle F., Massé E., Dozois C.M. The small RNA RyhB contributes to siderophore production and virulence of uropathogenic Escherichia coli. Infect. Immun. 2014;82:5056-5068.

    Not in our library10.1128/iai.02287-14

  115. 115.

    Hagan E.C., Mobley H.L. Haem acquisition is facilitated by a novel receptor Hma and required by uropathogenic Escherichia coli for kidney infection. Mol. Microbiol. 2009;71:79-91.

    Not in our library10.1111/j.1365-2958.2008.06509.x

  116. 116.

    Stojiljkovic I., Perkins-Balding D. Processing of heme and heme-containing proteins by bacteria. DNA Cell Biol. 2002;21:281-295.

    Not in our library10.1089/104454902753759708

  117. 117.
    Quantitative Metabolomics Reveals an Epigenetic Blueprint for Iron Acquisition in Uropathogenic Escherichia coli · 2009
    No notice
  118. 118.

    Raffatellu M., George M.D., Akiyama Y., Hornsby M.J., Nuccio S.P., Paixao T.A., Butler B.P., Chu H., Santos R.L., Berger T., et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe. 2009;5:476-486.

    Not in our library10.1016/j.chom.2009.03.011

  119. 119.

    Valdebenito M., Crumbliss A.L., Winkelmann G., Hantke K. Environmental factors influence the production of enterobactin, salmochelin, aerobactin, and yersiniabactin in Escherichia coli strain Nissle 1917. Int. J. Med. Microbiol. 2006;296:513-520.

    Not in our library10.1016/j.ijmm.2006.06.003

  120. 120.

    Feldmann F., Sorsa L.J., Hildinger K., Schubert S. The salmochelin siderophore receptor IroN contributes to invasion of urothelial cells by extraintestinal pathogenic Escherichia coli in vitro. Infect. Immun. 2007;75:3183-3187.

    Not in our library10.1128/iai.00656-06

  121. 121.

    Russo T.A., Mcfadden C.D., Carlino-Macdonald U.B., Beanan J.M., Olson R., Wilding G.E. The Siderophore Receptor IroN of Extraintestinal Pathogenic Escherichia coli Is a Potential Vaccine Candidate. Infect. Immun. 2003;71:7164-7169.

    Not in our library10.1128/iai.71.12.7164-7169.2003

  122. 122.

    Chaturvedi K.S., Hung C.S., Crowley J.R., Stapleton A.E., Henderson J.P. The siderophore yersiniabactin binds copper to protect pathogens during infection. Nat. Chem. Biol. 2012;8:731-736.

    Not in our library10.1038/nchembio.1020

  123. 123.

    Reigstad C.S., Hultgren S.J., Gordon J.I. Functional genomic studies of uropathogenic Escherichia coli and host urothelial cells when intracellular bacterial communities are assembled. J. Biol. Chem. 2007;282:21259-21267.

    Not in our library10.1074/jbc.m611502200

  124. 124.

    Watts R.E., Totsika M., Challinor V.L., Mabbett A.N., Ulett G.C., De Voss J.J., Schembri M.A. Contribution of siderophore systems to growth and urinary tract colonization of asymptomatic bacteriuria Escherichia coli. Infect. Immun. 2012;80:333-344.

    Not in our library10.1128/iai.05594-11

  125. 125.

    Garcia E.C., Brumbaugh A.R., Mobley H.L. Redundancy and specificity of Escherichia coli iron acquisition systems during urinary tract infection. Infect. Immun. 2011;79:1225-1235.

    Not in our library10.1128/iai.01222-10

  126. 126.

    Torres A.G., Redford P., Welch R.A., Payne S.M. TonB-dependent systems of uropathogenic Escherichia coli: Aerobactin and heme transport and TonB are required for virulence in the mouse. Infect. Immun. 2001;69:6179-6185.

    Not in our library10.1128/iai.69.10.6179-6185.2001

  127. 127.

    Justice S.S., Hung C., Theriot J.A., Fletcher D.A., Anderson G.G., Footer M.J., Hultgren S.J. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Natl. Acad. Sci. USA. 2004;101:1333-1338.

    Not in our library10.1073/pnas.0308125100

  128. 128.
    Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection · 2007
    No notice
  129. 129.

    Anderson G.G., Martin S.M., Hultgren S.J. Host subversion by formation of intracellular bacterial communities in the urinary tract. Microbes Infect. 2004;6:1094-1101.

    Not in our library10.1016/j.micinf.2004.05.023

  130. 130.

    Eto D.S., Sundsbak J.L., Mulvey M.A. Actin-gated intracellular growth and resurgence of uropathogenic Escherichia coli. Cell Microbiol. 2006;8:704-717.

    Not in our library10.1111/j.1462-5822.2006.00691.x

  131. 131.

    Leatham-Jensen M.P., Mokszycki M.E., Rowley D.C., Deering R., Camberg J.L., Sokurenko E.V., Tchesnokova V.L., Frimodt-Møller J., Krogfelt K.A., Leth Nielsen K., et al. Uropathogenic Escherichia coli Metabolite-Dependent Quiescence and Persistence May Explain Antibiotic Tolerance during Urinary Tract Infection. mSphere. 2016;1:e00055-15.

    Not in our library10.1128/msphere.00055-15

  132. 132.

    Goetz D.H., Holmes M.A., Borregaard N., Bluhm M.E., Raymond K.N., Strong R.K. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell. 2002;10:1033-1043.

    Not in our library10.1016/s1097-2765(02)00708-6

  133. 133.

    Fischbach M.A., Lin H., Zhou L., Yu Y., Abergel R.J., Liu D.R., Raymond K.N., Wanner B.L., Strong R.K., Walsh C.T., et al. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc. Natl. Acad. Sci. USA. 2006;103:16502-16507.

    Not in our library10.1073/pnas.0604636103

  134. 134.

    Smith K.D. Iron metabolism at the host pathogen interface: Lipocalin 2 and the pathogen-associated iroA gene cluster. Int. J. Biochem. Cell Biol. 2007;39:1776-1780.

    Not in our library10.1016/j.biocel.2007.07.003

  135. 135.

    Simpson B.W., May J.M., Sherman D.J., Kahne D., Ruiz N. Lipopolysaccharide transport to the cell surface: Biosynthesis and extraction from the inner membrane. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015;370:20150029.

    Not in our library10.1098/rstb.2015.0029

  136. 136.

    Maldonado R.F., Sá-Correia I., Valvano M.A. Lipopolysaccharide modification in Gram-negative bacteria during chronic infection. FEMS Microbiol. Rev. 2016;40:480-493.

    Not in our library10.1093/femsre/fuw007

  137. 137.

    Billips B.K., Schaeffer A.J., Klumpp D.J. Molecular basis of uropathogenic Escherichia coli evasion of the innate immune response in the bladder. Infect. Immun. 2008;76:3891-3900.

    Not in our library10.1128/iai.00069-08

  138. 138.

    Hunstad D.A., Justice S.S., Hung C.S., Lauer S.R., Hultgren S.J. Suppression of bladder epithelial cytokine responses by uropathogenic Escherichia coli. Infect. Immun. 2005;73:3999-4006.

    Not in our library10.1128/iai.73.7.3999-4006.2005

  139. 139.

    Jacobson S.H., Ostenson C.G., Tullus K., Brauner A. Serum resistance in Escherichia coli strains causing acute pyelonephritis and bacteraemia. Apmis. 1992;100:147-153.

    Not in our library10.1111/j.1699-0463.1992.tb00854.x

  140. 140.

    Fux C.A., Costerton J.W., Stewart P.S., Stoodley P. Survival strategies of infectious biofilms. Trends Microbiol. 2005;13:34-40.

    Not in our library10.1016/j.tim.2004.11.010

  141. 141.

    Costerton J.W., Stewart P.S., Greenberg E.P. Bacterial biofilms: A common cause of persistent infections. Science. 1999;284:1318-1322.

    Not in our library10.1126/science.284.5418.1318

  142. 142.

    Ejrnæs K., Stegger M., Reisner A., Ferry S., Monsen T., Holm S.E., Lundgren B., Frimodt-Møller N. Characteristics of Escherichia coli causing persistence or relapse of urinary tract infections: Phylogenetic groups, virulence factors and biofilm formation. Virulence. 2011;2:528-537.

    Not in our library10.4161/viru.2.6.18189

  143. 143.

    Norinder B.S., Lüthje P., Yadav M., Kadas L., Fang H., Nord C.E., Brauner A. Cellulose and PapG are important for Escherichia coli causing recurrent urinary tract infection in women. Infection. 2011;39:571-574.

    Not in our library10.1007/s15010-011-0199-0

  144. 144.

    Salo J., Sevander J.J., Tapiainen T., Ikäheimo I., Pokka T., Koskela M., Uhari M. Biofilm formation by Escherichia coli isolated from patients with urinary tract infections. Clin. Nephrol. 2009;71:501-507.

    Not in our library10.5414/cnp71501

  145. 145.

    Tapiainen T., Hanni A.M., Salo J., Ikäheimo I., Uhari M. Escherichia coli biofilm formation and recurrences of urinary tract infections in children. Eur. J. Clin. Microbiol. Infect. Dis. 2014;33:111-115.

    Not in our library10.1007/s10096-013-1935-4

  146. 146.

    Bahrani-Mougeot F.K., Buckles E.L., Lockatell C.V., Hebel J.R., Johnson D.E., Tang C.M., Donnenberg M.S. Type 1 fimbriae and extracellular polysaccharides are preeminent uropathogenic Escherichia coli virulence determinants in the murine urinary tract. Mol. Microbiol. 2002;45:1079-1093.

    Not in our library10.1046/j.1365-2958.2002.03078.x

  147. 147.
    Genome-Wide Detection of Fitness Genes in Uropathogenic Escherichia coli during Systemic Infection · 2013
    No notice
  148. 148.

    Conway C., Beckett M.C., Dorman C.J. The DNA relaxation-dependent OFF-to-ON biasing of the type 1 fimbrial genetic switch requires the Fis nucleoid-associated protein. Microbiology. 2023;169:001283.

    Not in our library10.1099/mic.0.001283

  149. 149.

    Bryan A., Roesch P., Davis L., Moritz R., Pellett S., Welch R.A. Regulation of type 1 fimbriae by unlinked FimB- and FimE-like recombinases in uropathogenic Escherichia coli strain CFT073. Infect. Immun. 2006;74:1072-1083.

    Not in our library10.1128/iai.74.2.1072-1083.2006

  150. 150.

    Foxman B. The epidemiology of urinary tract infection. Nat. Rev. Urol. 2010;7:653-660.

    Not in our library10.1038/nrurol.2010.190

  151. 151.

    Gupta K., Grigoryan L., Trautner B. Urinary Tract Infection. Ann. Intern. Med. 2017;167:Itc49-Itc64.

    Not in our library10.7326/aitc201710030

  152. 152.

    Chu C.M., Lowder J.L. Diagnosis and treatment of urinary tract infections across age groups. Am. J. Obstet. Gynecol. 2018;219:40-51.

    Not in our library10.1016/j.ajog.2017.12.231

  153. 153.

    Muller A.E., Verhaegh E.M., Harbarth S., Mouton J.W., Huttner A. Nitrofurantoin’s efficacy and safety as prophylaxis for urinary tract infections: A systematic review of the literature and meta-analysis of controlled trials. Clin. Microbiol. Infect. 2017;23:355-362.

    Not in our library10.1016/j.cmi.2016.08.003

  154. 154.

    Davis W.H., Magee M.R., Monks S.M., Geno K.A., Crawford S.B. Assessment of nationally recommended antibiotics for treatment of UTI in U.S.-Mexico border emergency departments. Am. J. Emerg. Med. 2022;61:12-17.

    Not in our library10.1016/j.ajem.2022.08.023

  155. 155.

    Gupta K., Hooton T.M., Roberts P.L., Stamm W.E. Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. Arch. Intern. Med. 2007;167:2207-2212.

    Not in our library10.1001/archinte.167.20.2207

  156. 156.

    Moya-Dionisio V., Díaz-Zabala M., Ibáñez-Fernández A., Suárez-Leiva P., Martínez-Suárez V., Ordóñez-Álvarez F.A., Santos-Rodríguez F. Uropathogen pattern and antimicrobial susceptibility in positive urinary cultures isolates from paediatric patients. Rev. Esp. Quimioter. 2016;29:146-150.

    Not in our library

  157. 157.

    Nicolle L.E. Pivmecillinam in the treatment of urinary tract infections. J. Antimicrob. Chemother. 2000;46:35-65.

    Not in our library10.1093/jac/46.suppl_1.35

  158. 158.

    Bader M.S., Loeb M., Leto D., Brooks A.A. Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents. Postgrad. Med. 2020;132:234-250.

    Not in our library10.1080/00325481.2019.1680052

  159. 159.

    Quek W.M., Teng C.B., Tan Y.Z., Chong K., Lye D.C., Ng T.M. Outcomes of Fosfomycin Use in Ceftriaxone-Resistant Enterobacteriaceae Urinary Tract Infection in the Elderly. Int. J. Antimicrob. Agents. 2019;53:195-196.

    Not in our library10.1016/j.ijantimicag.2018.10.008

  160. 160.

    Peretz A., Naamneh B., Tkhawkho L., Nitzan O. High Rates of Fosfomycin Resistance in Gram-Negative Urinary Isolates from Israel. Microb. Drug. Resist. 2019;25:408-412.

    Not in our library10.1089/mdr.2018.0393

  161. 161.

    Gupta K., Hooton T.M., Naber K.G., Wullt B., Colgan R., Miller L.G., Moran G.J., Nicolle L.E., Raz R., Schaeffer A.J., et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin. Infect. Dis. 2011;52:e103-e120.

    Not in our library10.1093/cid/ciq257

  162. 162.

    Chen Y.H., Ko W.C., Hsueh P.R. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin. Pharm. 2013;14:587-596.

    Not in our library10.1517/14656566.2013.778827

  163. 163.

    Paterson D.L. Resistance in gram-negative bacteria: Enterobacteriaceae. Am. J. Med. 2006;34:S20-S70.

    Not in our library10.1016/j.amjmed.2006.03.013

  164. 164.

    Pendleton J.N., Gorman S.P., Gilmore B.F. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti. Infect. Ther. 2013;11:297-308.

    Not in our library10.1586/eri.13.12

  165. 165.

    Gupta K., Bhadelia N. Management of urinary tract infections from multidrug-resistant organisms. Infect. Dis. Clin. N. Am. 2014;28:49-59.

    Not in our library10.1016/j.idc.2013.10.002

  166. 166.

    Bader M.S., Loeb M., Brooks A.A. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgrad. Med. 2017;129:242-258.

    Not in our library10.1080/00325481.2017.1246055

  167. 167.

    Garau J. Other antimicrobials of interest in the era of extended-spectrum beta-lactamases: Fosfomycin, nitrofurantoin and tigecycline. Clin. Microbiol. Infect. 2008;14:198-202.

    Not in our library10.1111/j.1469-0691.2007.01852.x

  168. 168.

    Paterson D.L., Bonomo R.A. Extended-spectrum beta-lactamases: A clinical update. Clin. Microbiol. Rev. 2005;18:657-686.

    Not in our library10.1128/cmr.18.4.657-686.2005

  169. 169.

    Bradford P.A. Extended-spectrum beta-lactamases in the 21st century: Characterization, epidemiology, and detection of this important resistance threat. Clin. Microbiol. Rev. 2001;14:933-951.

    Not in our library10.1128/cmr.14.4.933-951.2001

  170. 170.

    Chang U.I., Kim H.W., Wie S.H. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J. Intern. Med. 2016;31:145-155.

    Not in our library10.3904/kjim.2016.31.1.145

  171. 171.

    Whelan S., O’Grady M.C., Corcoran G.D., Finn K., Lucey B. Effect of Sub-Inhibitory Concentrations of Nitrofurantoin, Ciprofloxacin, and Trimethoprim on In Vitro Biofilm Formation in Uropathogenic Escherichia coli (UPEC). Med. Sci. 2022;11:1.

    Not in our library10.3390/medsci11010001

  172. 172.

    Walker G.K., Suyemoto M.M., Hull D.M., Gall S., Jimenez F., Chen L.R., Thakur S., Crespo R., Borst L.B. Genomic Characterization of a Nalidixic Acid-Resistant Salmonella Enteritidis Strain Causing Persistent Infections in Broiler Chickens. Front. Vet. Sci. 2021;8:725737.

    Not in our library10.3389/fvets.2021.725737

  173. 173.

    Khan A., Jabeen H., Ahmad T., Rehman N.U., Khan S.S., Shareef H., Sarwar R., Yahya S., Hussain N., Uddin J., et al. Comparative efficacy of cephradine-loaded silver and gold nanoparticles against resistant human pathogens. Artif. Cells Nanomed. Biotechnol. 2022;50:312-321.

    Not in our library10.1080/21691401.2022.2144340

  174. 174.

    Millner R., Becknell B. Urinary Tract Infections. Pediatr. Clin. N. Am. 2019;66:1-13.

    Not in our library10.1016/j.pcl.2018.08.002

  175. 175.

    Zalewska-Piątek B.M., Piątek R.J. Alternative treatment approaches of urinary tract infections caused by uropathogenic Escherichia coli strains. Acta Biochim. Pol. 2019;66:129-138.

    Not in our library10.18388/abp.2018_2787

  176. 176.

    Saatchi A., Yoo J.W., Schwartz K.L., Silverman M., Morris A.M., Patrick D.M., McCormack J., Marra F. Quantifying the Gap between Expected and Actual Rates of Antibiotic Prescribing in British Columbia, Canada. Antibiotics. 2021;10:1428.

    Not in our library10.3390/antibiotics10111428

  177. 177.

    McLellan L.K., Hunstad D.A. Urinary Tract Infection: Pathogenesis and Outlook. Trends Mol. Med. 2016;22:946-957.

    Not in our library10.1016/j.molmed.2016.09.003

  178. 178.

    Grischke E.M., Rüttgers H. Treatment of bacterial infections of the female urinary tract by immunization of the patients. Urol. Int. 1987;42:338-341.

    Not in our library10.1159/000281988

  179. 179.

    Hopkins W.J., Elkahwaji J., Beierle L.M., Leverson G.E., Uehling D.T. Vaginal mucosal vaccine for recurrent urinary tract infections in women: Results of a phase 2 clinical trial. J. Urol. 2007;177:1349-1353.

    Not in our library10.1016/j.juro.2006.11.093

  180. 180.

    Beerepoot M.A., Geerlings S.E., van Haarst E.P., van Charante N.M., ter Riet G. Nonantibiotic prophylaxis for recurrent urinary tract infections: A systematic review and meta-analysis of randomized controlled trials. J. Urol. 2013;190:1981-1989.

    Not in our library10.1016/j.juro.2013.04.142

  181. 181.

    Kochiashvili D., Khuskivadze A., Kochiashvili G., Koberidze G., Kvakhajelidze V. Role of the bacterial vaccine Solco-Urovac® in treatment and prevention of recurrent urinary tract infections of bacterial origin. Georgian. Med. News. 2014;231:11-16.

    Not in our library

  182. 182.

    Wade D., Cooper J., Derry F., Taylor J. Uro-Vaxom® versus placebo for the prevention of recurrent symptomatic urinary tract infections in participants with chronic neurogenic bladder dysfunction: A randomised controlled feasibility study. Trials. 2019;20:223.

    Not in our library10.1186/s13063-019-3275-x

  183. 183.

    Magasi P., Pánovics J., Illés A., Nagy M. Uro-Vaxom and the management of recurrent urinary tract infection in adults: A randomized multicenter double-blind trial. Eur. Urol. 1994;26:137-140.

    Not in our library10.1159/000475363

  184. 184.

    Cruz F., Dambros M., Naber K.G., Bauer H.W., Cozma G. Recurrent Urinary Tract Infections: Uro-Vaxom, a New Alternative. Eur. Urol. Suppl. 2009;8:762-768.

    Not in our library10.1016/j.eursup.2009.07.002

  185. 185.

    Kim K.S., Kim J.Y., Jeong I.G., Paick J.S., Son H., Lim D.J., Shim H.B., Park W.H., Jung H.C., Choo M.S. A prospective multi-center trial of Escherichia coli extract for the prophylactic treatment of patients with chronically recurrent cystitis. J. Korean Med. Sci. 2010;25:435-439.

    Not in our library10.3346/jkms.2010.25.3.435

  186. 186.

    Magistro G., Stief C.G. Vaccine Development for Urinary Tract Infections: Where Do We Stand? Eur. Urol. Focus. 2019;5:39-41.

    Not in our library10.1016/j.euf.2018.07.034

  187. 187.

    Marinova S., Nenkov P., Markova R., Nikolaeva S., Kostadinova R., Mitov I., Vretenarska M. Cellular and humoral systemic and mucosal immune responses stimulated by an oral polybacterial immunomodulator in patients with chronic urinary tract infections. Int. J. Immunopathol. Pharmacol. 2005;18:457-473.

    Not in our library10.1177/039463200501800306

  188. 188.

    Del Bino L., Østerlid K.E., Wu D.Y., Nonne F., Romano M.R., Codée J., Adamo R. Synthetic Glycans to Improve Current Glycoconjugate Vaccines and Fight Antimicrobial Resistance. Chem. Rev. 2022;122:15672-15716.

    Not in our library10.1021/acs.chemrev.2c00021

  189. 189.

    Russo T.A., Beanan J.M., Olson R., MacDonald U., Cope J.J. Capsular polysaccharide and the O-specific antigen impede antibody binding: A potential obstacle for the successful development of an extraintestinal pathogenic Escherichia coli vaccine. Vaccine. 2009;27:388-395.

    Not in our library10.1016/j.vaccine.2008.10.082

  190. 190.

    Billips B.K., Yaggie R.E., Cashy J.P., Schaeffer A.J., Klumpp D.J. A live-attenuated vaccine for the treatment of urinary tract infection by uropathogenic Escherichia coli. J. Infect. Dis. 2009;200:263-272.

    Not in our library10.1086/599839

  191. 191.

    Horvath D.J., Patel A.S., Mohamed A., Storm D.W., Singh C., Li B., Zhang J., Koff S.A., Jayanthi V.R., Mason K.M., et al. Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract. J. Bacteriol. 2016;198:964-972.

    Not in our library10.1128/jb.00664-15

  192. 192.

    Uehling D.T., Hopkins W.J., Dahmer L.A., Balish E. Phase I clinical trial of vaginal mucosal immunization for recurrent urinary tract infection. J. Urol. 1994;152:2308-2311.

    Not in our library10.1016/s0022-5347(17)31664-6

  193. 193.

    Uehling D.T., Hopkins W.J., Elkahwaji J.E., Schmidt D.M., Leverson G.E. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J. Urol. 2003;170:867-869.

    Not in our library10.1097/01.ju.0000075094.54767.6e

  194. 194.

    Russo T.A., Beanan J.M., Olson R., Genagon S.A., MacDonald U., Cope J.J., Davidson B.A., Johnston B., Johnson J.R. A killed, genetically engineered derivative of a wild-type extraintestinal pathogenic E. coli strain is a vaccine candidate. Vaccine. 2007;25:3859-3870.

    Not in our library10.1016/j.vaccine.2007.01.100

  195. 195.

    Billips B.K., Forrestal S.G., Rycyk M.T., Johnson J.R., Klumpp D.J., Schaeffer A.J. Modulation of host innate immune response in the bladder by uropathogenic Escherichia coli. Infect Immun. 2007;75:5353-5360.

    Not in our library10.1128/iai.00922-07

  196. 196.

    William B.S., Darren A., Bart S., Oscar G., Wouter H., Tiziano D.R., Kellen F., Jan P., Stefan T., Ibarra D. 2712. Safety and Immunogenicity of two Doses of ExPEC4V Vaccine Against Extraintestinal Pathogenic Escherichia coli Disease in Healthy Adult Participants. Open Forum Infect. Dis. 2019;6:S954.

    Not in our library

  197. 197.

    Frenck R.W., Ervin J., Chu L., Abbanat D., Spiessens B., Go O., Haazen W., van den Dobbelsteen G., Poolman J., Thoelen S., et al. Safety and immunogenicity of a vaccine for extra-intestinal pathogenic Escherichia coli (ESTELLA): A phase 2 randomised controlled trial. Lancet Infect. Dis. 2019;19:631-640.

    Not in our library10.1016/s1473-3099(18)30803-x

  198. 198.

    Asadi Karam M.R., Oloomi M., Mahdavi M., Habibi M., Bouzari S. Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice. Vaccine. 2013;31:1210-1216.

    Not in our library10.1016/j.vaccine.2012.12.059

  199. 199.

    Hasanzadeh S., Habibi M., Shokrgozar M.A., Ahangari Cohan R., Ahmadi K., Asadi Karam M.R., Bouzari S. In silico analysis and in vivo assessment of a novel epitope-based vaccine candidate against uropathogenic Escherichia coli. Sci. Rep. 2020;10:16258.

    Not in our library10.1038/s41598-020-73179-w

  200. 200.

    Asadi Karam M.R., Habibi M., Bouzari S. Urinary tract infection: Pathogenicity, antibiotic resistance and development of effective vaccines against Uropathogenic Escherichia coli. Mol. Immunol. 2019;108:56-67.

    Not in our library10.1016/j.molimm.2019.02.007

  201. 201.

    Savar N.S., Jahanian-Najafabadi A., Mahdavi M., Shokrgozar M.A., Jafari A., Bouzari S. In silico and in vivo studies of truncated forms of flagellin (FliC) of enteroaggregative Escherichia coli fused to FimH from uropathogenic Escherichia coli as a vaccine candidate against urinary tract infections. J. Biotechnol. 2014;175:31-37.

    Not in our library10.1016/j.jbiotec.2014.01.037

  202. 202.

    Asadi Karam M.R., Habibi M., Bouzari S. Use of flagellin and cholera toxin as adjuvants in intranasal vaccination of mice to enhance protective immune responses against uropathogenic Escherichia coli antigens. Biologicals. 2016;44:378-386.

    Not in our library10.1016/j.biologicals.2016.06.006

  203. 203.

    Habibi M., Asadi Karam M.R., Bouzari S. Evaluation of prevalence, immunogenicity and efficacy of FyuA iron receptor in uropathogenic Escherichia coli isolates as a vaccine target against urinary tract infection. Microb. Pathog. 2017;110:477-483.

    Not in our library10.1016/j.micpath.2017.07.037

  204. 204.

    Brumbaugh A.R., Smith S.N., Mobley H.L. Immunization with the yersiniabactin receptor, FyuA, protects against pyelonephritis in a murine model of urinary tract infection. Infect. Immun. 2013;81:3309-3316.

    Not in our library10.1128/iai.00470-13

  205. 205.

    Huttner A., Hatz C., van den Dobbelsteen G., Abbanat D., Hornacek A., Frölich R., Dreyer A.M., Martin P., Davies T., Fae K., et al. Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: A randomised, single-blind, placebo-controlled phase 1b trial. Lancet Infect. Dis. 2017;17:528-537.

    Not in our library10.1016/s1473-3099(17)30108-1

  206. 206.

    Langermann S., Palaszynski S., Barnhart M., Auguste G., Pinkner J.S., Burlein J., Barren P., Koenig S., Leath S., Jones C.H., et al. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science. 1997;276:607-611.

    Not in our library10.1126/science.276.5312.607

  207. 207.

    Poggio T.V., La Torre J.L., Scodeller E.A. Intranasal immunization with a recombinant truncated FimH adhesin adjuvanted with CpG oligodeoxynucleotides protects mice against uropathogenic Escherichia coli challenge. Can. J. Microbiol. 2006;52:1093-1102.

    Not in our library10.1139/w06-065

  208. 208.

    Karam M.R., Oloomi M., Mahdavi M., Habibi M., Bouzari S. Assessment of immune responses of the flagellin (FliC) fused to FimH adhesin of Uropathogenic Escherichia coli. Mol. Immunol. 2013;54:32-39.

    Not in our library10.1016/j.molimm.2012.11.002

  209. 209.

    Bagherpour G., Fooladi A.A., Mehrabadi J.F., Nourani M.R., Einollahi B. Evaluation of mammalian codon usage of fimH in DNA vaccine design. Acta Microbiol. Immunol. Hung. 2011;58:259-271.

    Not in our library10.1556/amicr.58.2011.4.2

  210. 210.

    Ferraro B., Morrow M.P., Hutnick N.A., Shin T.H., Lucke C.E., Weiner D.B. Clinical applications of DNA vaccines: Current progress. Clin. Infect. Dis. 2011;53:296-302.

    Not in our library10.1093/cid/cir334

  211. 211.

    Imani Fooladi A.A., Bagherpour G., Khoramabadi N., Fallah Mehrabadi J., Mahdavi M., Halabian R., Amin M., Izadi Mobarakeh J., Einollahi B. Cellular immunity survey against urinary tract infection using pVAX/fimH cassette with mammalian and wild type codon usage as a DNA vaccine. Clin. Exp. Vaccine Res. 2014;3:185-193.

    Not in our library10.7774/cevr.2014.3.2.185

  212. 212.

    Roberts J.A., Kaack M.B., Baskin G., Chapman M.R., Hunstad D.A., Pinkner J.S., Hultgren S.J. Antibody responses and protection from pyelonephritis following vaccination with purified Escherichia coli PapDG protein. J. Urol. 2004;171:1682-1685.

    Not in our library10.1097/01.ju.0000116123.05160.43

  213. 213.

    Mike L.A., Smith S.N., Sumner C.A., Eaton K.A., Mobley H.L. Siderophore vaccine conjugates protect against uropathogenic Escherichia coli urinary tract infection. Proc. Natl. Acad. Sci. USA. 2016;113:13468-13473.

    Not in our library10.1073/pnas.1606324113

  214. 214.

    Wieser A., Romann E., Magistro G., Hoffmann C., Nörenberg D., Weinert K., Schubert S. A multiepitope subunit vaccine conveys protection against extraintestinal pathogenic Escherichia coli in mice. Infect. Immun. 2010;78:3432-3442.

    Not in our library10.1128/iai.00174-10

  215. 215.

    Wieser A., Magistro G., Nörenberg D., Hoffmann C., Schubert S. First multi-epitope subunit vaccine against extraintestinal pathogenic Escherichia coli delivered by a bacterial type-3 secretion system (T3SS). Int. J. Med. Microbiol. 2012;302:10-18.

    Not in our library10.1016/j.ijmm.2011.09.012

  216. 216.
    Mucosal Immunization with Iron Receptor Antigens Protects against Urinary Tract Infection · 2009
    No notice
  217. 217.

    Cole S.T. Who will develop new antibacterial agents? Philos. Trans. R. Soc. Lond. B Biol. Sci. 2014;369:20130430.

    Not in our library10.1098/rstb.2013.0430

  218. 218.

    Marouf R.S., Mbarga J.A.M., Ermolaev A.V., Podoprigora I.V., Smirnova I.P., Yashina N.V., Zhigunova A.V., Martynenkova A.V. Antibacterial Activity of Medicinal Plants against Uropathogenic Escherichia coli. J. Pharm. Bioallied. Sci. 2022;14:1-12.

    Not in our library10.4103/jpbs.jpbs_124_21

  219. 219.

    Shaheen G., Akram M., Jabeen F., Ali Shah S.M., Munir N., Daniyal M., Riaz M., Tahir I.M., Ghauri A.O., Sultana S., et al. Therapeutic potential of medicinal plants for the management of urinary tract infection: A systematic review. Clin. Exp. Pharmacol. Physiol. 2019;46:613-624.

    Not in our library10.1111/1440-1681.13092

  220. 220.

    Álvarez-Martínez F.J., Barrajón-Catalán E., Encinar J.A., Rodríguez-Díaz J.C., Micol V. Antimicrobial Capacity of Plant Polyphenols against Gram-positive Bacteria: A Comprehensive Review. Curr. Med. Chem. 2020;27:2576-2606.

    Not in our library10.2174/0929867325666181008115650

  221. 221.

    Álvarez-Martínez F.J., Rodríguez J.C., Borrás-Rocher F., Barrajón-Catalán E., Micol V. The antimicrobial capacity of Cistus salviifolius and Punica granatum plant extracts against clinical pathogens is related to their polyphenolic composition. Sci. Rep. 2021;11:588.

    Not in our library10.1038/s41598-020-80003-y

  222. 222.

    Upadhyay A., Upadhyaya I., Kollanoor-Johny A., Venkitanarayanan K. Combating pathogenic microorganisms using plant-derived antimicrobials: A minireview of the mechanistic basis. Biomed. Res. Int. 2014;2014:761741.

    Not in our library10.1155/2014/761741

  223. 223.
    Review on plant antimicrobials: a mechanistic viewpoint · 2019
    No notice
  224. 224.

    Deipenbrock M., Hensel A. Polymethoxylated flavones from Orthosiphon stamineus leaves as antiadhesive compounds against uropathogenic E. coli. Fitoterapia. 2019;139:104387.

    Not in our library10.1016/j.fitote.2019.104387

  225. 225.

    Sarshar S., Sendker J., Qin X., Goycoolea F.M., Asadi Karam M.R., Habibi M., Bouzari S., Dobrindt U., Hensel A. Antiadhesive hydroalcoholic extract from Apium graveolens fruits prevents bladder and kidney infection against uropathogenic E. coli. Fitoterapia. 2018;127:237-244.

    Not in our library10.1016/j.fitote.2018.02.029

  226. 226.

    Scharf B., Sendker J., Dobrindt U., Hensel A. Influence of Cranberry Extract on Tamm-Horsfall Protein in Human Urine and its Antiadhesive Activity Against Uropathogenic Escherichia coli. Planta Med. 2019;85:126-138.

    Not in our library10.1055/a-0755-7801

  227. 227.

    Mutters N.T., Mampel A., Kropidlowski R., Biehler K., Günther F., Bălu I., Malek V., Frank U. Treating urinary tract infections due to MDR E. coli with Isothiocyanates—A phytotherapeutic alternative to antibiotics? Fitoterapia. 2018;129:237-240.

    Not in our library10.1016/j.fitote.2018.07.012

  228. 228.

    Sabadash M., Shulyak A. Canephron® N in the treatment of recurrent cystitis in women of child-bearing Age: A randomised controlled study. Clin. Phyt. 2017;3:9.

    Not in our library10.1186/s40816-017-0046-7

  229. 229.

    Vacheva A., Mustafa B., Staneva J., Marhova M., Kostadinova S., Todorova M., Ivanova R., Stoitsova S. Effects of Extracts from Medicinal Plants on Biofilm Formation by Escherichia coli Urinary Tract Isolates. Biotechnol. Biotechnol. Equip. 2011;25:92-97.

    Not in our library10.5504/bbeq.2011.0111

  230. 230.

    Žitek T., Postružnik V., Knez Ž., Golle A., Dariš B., Knez Marevci M., Arnica Montana L. Supercritical Extraction Optimization for Antibiotic and Anticancer Activity. Front. Bioeng. Biotechnol. 2022;10:897185.

    Not in our library10.3389/fbioe.2022.897185

  231. 231.

    Hidalgo G., Chan M., Tufenkji N. Inhibition of Escherichia coli CFT073 fliC expression and motility by cranberry materials. Appl. Environ. Microbiol. 2011;77:6852-6857.

    Not in our library10.1128/aem.05561-11

  232. 232.

    Ranfaing J., Dunyach-Remy C., Lavigne J.P., Sotto A. Propolis potentiates the effect of cranberry (Vaccinium macrocarpon) in reducing the motility and the biofilm formation of uropathogenic Escherichia coli. PLoS ONE. 2018;13:e0202609.

    Not in our library10.1371/journal.pone.0202609

  233. 233.

    Rosenberg S., Horowitz R., Coppenhagen-Glazer S., Pizov G., Elia A., Gofrit O.N., Ginsburg I., Pode D. Intravesical administration of green tea extract attenuates the inflammatory response of bacterial cystitis–a rat model. BJU Int. 2014;114:601-607.

    Not in our library10.1111/bju.12544

  234. 234.

    Zhou S., Fan K.K., Gu L.F., Yu B.Y., Chai C.Z. Anti-inflammatory effects of Abelmoschus manihot (L.) Medik. on LPS-induced cystitis in mice: Potential candidate for cystitis treatment based on classic use. Chin. J. Nat. Med. 2022;20:321-331.

    Not in our library10.1016/s1875-5364(22)60140-7

  235. 235.

    Rafsanjany N., Lechtenberg M., Petereit F., Hensel A. Antiadhesion as a functional concept for protection against uropathogenic Escherichia coli: In vitro studies with traditionally used plants with antiadhesive activity against uropathognic Escherichia coli. J. Ethnopharmacol. 2013;145:591-597.

    Not in our library10.1016/j.jep.2012.11.035

  236. 236.

    Bortolami M., Di Matteo P., Rocco D., Feroci M., Petrucci R. Metabolic Profile of Agropyron repens (L.) P. Beauv. Rhizome Herbal Tea by HPLC-PDA-ESI-MS/MS Analysis. Molecules. 2022;27:4962.

    Not in our library10.3390/molecules27154962

  237. 237.

    Noundou X.S., Krause R.W., van Vuuren S.F., Ndinteh D.T., Olivier D.K. Antibacterial effects of Alchornea cordifolia (Schumach. and Thonn.) Müll. Arg extracts and compounds on gastrointestinal, skin, respiratory and urinary tract pathogens. J. Ethnopharmacol. 2016;179:76-82.

    Not in our library10.1016/j.jep.2015.12.043

  238. 238.

    Lee K.C., Chang H.H., Chung Y.H., Lee T.Y. Andrographolide acts as an anti-inflammatory agent in LPS-stimulated RAW264.7 macrophages by inhibiting STAT3-mediated suppression of the NF-κB pathway. J. Ethnopharmacol. 2011;135:678-684.

    Not in our library10.1016/j.jep.2011.03.068

  239. 239.

    de Arriba S.G., Naser B., Nolte K.U. Risk assessment of free hydroquinone derived from Arctostaphylos Uva-ursi folium herbal preparations. Int. J. Toxicol. 2013;32:442-453.

    Not in our library10.1177/1091581813507721

  240. 240.

    Dietz B.M., Hajirahimkhan A., Dunlap T.L., Bolton J.L. Botanicals and Their Bioactive Phytochemicals for Women’s Health. Pharmacol. Rev. 2016;68:1026-1073.

    Not in our library10.1124/pr.115.010843

  241. 241.

    Venkatadri B., Arunagirinathan N., Rameshkumar M.R., Ramesh L., Dhanasezhian A., Agastian P. In vitro Antibacterial Activity of Aqueous and Ethanol Extracts of Aristolochia indica and Toddalia asiatica Against Multidrug-Resistant Bacteria. Indian J. Pharm. Sci. 2015;77:788-791.

    Not in our library10.4103/0250-474x.174991

  242. 242.

    Michl J., Jennings H.M., Kite G.C., Ingrouille M.J., Simmonds M.S., Heinrich M. Is aristolochic acid nephropathy a widespread problem in developing countries? A case study of Aristolochia indica L. in Bangladesh using an ethnobotanical-phytochemical approach. J. Ethnopharmacol. 2013;149:235-244.

    Not in our library10.1016/j.jep.2013.06.028

  243. 243.

    Albrecht U., Goos K.H., Schneider B. A randomised, double-blind, placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent lower urinary tract infections. Curr. Med. Res. Opin. 2007;23:2415-2422.

    Not in our library10.1185/030079907x233089

  244. 244.

    Conrad A., Biehler D., Nobis T., Richter H., Engels I., Biehler K., Frank U. Broad spectrum antibacterial activity of a mixture of isothiocyanates from nasturtium (Tropaeoli majoris herba) and horseradish (Armoraciae rusticanae radix). Drug. Res. 2013;63:65-68.

    Not in our library10.1055/s-0032-1331754

  245. 245.

    Rajkumar J., Devi A.S., Beenish T.K. Detection of Antibacterial Compound of Avicennia marina Against Pathogens Isolated from Urinary Tract Infected Patients. Asian J. Chem. 2014;26:458-460.

    Not in our library

  246. 246.

    Wojnicz D., Kucharska A.Z., Sokół-Łętowska A., Kicia M., Tichaczek-Goska D. Medicinal plants extracts affect virulence factors expression and biofilm formation by the uropathogenic Escherichia coli. Urol. Res. 2012;40:683-697.

    Not in our library10.1007/s00240-012-0499-6

  247. 247.

    Sahu L., Jena S., Swain S.S., Sahoo S., Chand P.K. Agrobacterium rhizogenes-mediated transformation of a multi-medicinal herb, Boerhaavia diffusa L.: Optimization of the process and anti-microbial activity against bacterial pathogens causing urinary tract infections. Front. Life Sci. 2013;7:197-209.

    Not in our library10.1080/21553769.2013.879266

  248. 248.

    Ferreres F., Sousa C., Justin M., Valentão P., Andrade P.B., Llorach R., Rodrigues A., Seabra R.M., Leitão A. Characterisation of the phenolic profile of Boerhaavia diffusa L. by HPLC-PAD-MS/MS as a tool for quality control. Phytochem. Anal. 2005;16:451-458.

    Not in our library10.1002/pca.869

  249. 249.

    Adetutu A., Morgan W.A., Corcoran O. Ethnopharmacological survey and in vitro evaluation of wound-healing plants used in South-western Nigeria. J. Ethnopharmacol. 2011;137:50-56.

    Not in our library10.1016/j.jep.2011.03.073

  250. 250.
    Bridelia ferruginea Benth.; An ethnomedicinal, phytochemical, pharmacological and toxicological review · 2022
    Not checked
  251. 251.

    Vučić D.M., Petković M.R., Rodić-Grabovac B.B., Stefanović O.D., Vasić S.M., Comić L.R. In vitro activity of heather [Calluna vulgaris (L.) Hull] extracts on selected urinary tract pathogens. Bosn. J. Basic Med. Sci. 2014;14:234-238.

    Not in our library10.17305/bjbms.2014.4.40

  252. 252.

    Vollmerhausen T.L., Ramos N.L., Dzung D.T., Brauner A. Decoctions from Citrus reticulata Blanco seeds protect the uroepithelium against Escherichia coli invasion. J. Ethnopharmacol. 2013;150:770-774.

    Not in our library10.1016/j.jep.2013.09.050

  253. 253.

    Duan L., Guo L., Dou L.L., Zhou C.L., Xu F.G., Zheng G.D., Li P., Liu E.H. Discrimination of Citrus reticulata Blanco and Citrus reticulata ‘Chachi’ by gas chromatograph-mass spectrometry based metabolomics approach. Food Chem. 2016;212:123-127.

    Not in our library10.1016/j.foodchem.2016.05.141

  254. 254.

    Uliana M.P., Silva A.G.D., Fronza M., Scherer R. In vitro Antioxidant and Antimicrobial Activities of Costus spicatus Swartz used in Folk Medicine for Urinary Tract Infection in Brazil. Latin. Am. J. Pharm. 2015;34:766-772.

    Not in our library

  255. 255.

    Chandra S., Gupta C.P. Antibacterial activity of medicinal plant Crateava nurvala (bark) against bacterial strains causing urinary tract infection. Asian J. Chem. 2001;13:1181-1186.

    Not in our library

  256. 256.

    Bhattacharjee A., Shashidhara S.C. Aswathanarayana, Phytochemical and ethno-pharmacological profile of Crataeva nurvala Buch-Hum (Varuna): A review. Asian Pac. J. Trop. Biomed. 2012;2:S1162-S1168.

    Not in our library10.1016/s2221-1691(12)60379-7

  257. 257.

    Packiavathy I.A., Priya S., Pandian S.K., Ravi A.V. Inhibition of biofilm development of uropathogens by curcumin—An anti-quorum sensing agent from Curcuma longa. Food Chem. 2014;148:453-460.

    Not in our library10.1016/j.foodchem.2012.08.002

  258. 258.

    Pereira R.S., Sumita T.C., Furlan M.R., Jorge A.O., Ueno M. Antibacterial activity of essential oils on microorganisms isolated from urinary tract infection. Rev. Saude Publica. 2004;38:326-328.

    Not in our library10.1590/s0034-89102004000200025

  259. 259.

    Sharma A., Verma R., Ramteke P. Cyperus rotundus: A potential novel source of therapeutic compound against urinary tract pathogens. J. Herb. Med. 2014;4:74-82.

    Not in our library10.1016/j.hermed.2014.01.003

  260. 260.

    Zhang X., Yan Y., Lv Y., Li X., Chen L., Huang Z., Zhou J., Wang Y., Wang X., Wang X., et al. Dendrobium officinale polysaccharides attenuate uropathogenic Escherichia coli (UPEC)-induced pyroptosis in macrophage cells. Biomed. Pharmacother. 2022;151:113098.

    Not in our library10.1016/j.biopha.2022.113098

  261. 261.

    Lüthje P., Lokman E.F., Sandström C., Östenson C., Brauner A. Gynostemma pentaphyllum exhibits anti-inflammatory properties and modulates antimicrobial peptide expression in the urinary bladder. J. Funct. Food. 2015;17:283-292.

    Not in our library10.1016/j.jff.2015.03.028

  262. 262.

    Fazliana M., Ramos N.L., Lüthje P., Sekikubo M., Holm A., Wan Nazaimoon W.M., Brauner A. Labisia pumila var. alata reduces bacterial load by inducing uroepithelial cell apoptosis. J. Ethnopharmacol. 2011;136:111-116.

    Not in our library10.1016/j.jep.2011.04.018

  263. 263.

    Lüthje P., Dzung D.N., Brauner A. Lactuca indica extract interferes with uroepithelial infection by Escherichia coli. J. Ethnopharmacol. 2011;135:672-677.

    Not in our library10.1016/j.jep.2011.03.069

  264. 264.

    Kim K.H., Lee K.H., Choi S.U., Kim Y.H., Lee K.R. Terpene and phenolic constituents of Lactuca indica L. Arch. Pharm. Res. 2008;31:983-988.

    Not in our library10.1007/s12272-001-1256-8

  265. 265.
    Orthosiphon stamineus Benth. is an outstanding food medicine: Review of phytochemical and pharmacological activities · 2018
    Not checked
  266. 266.

    Elmahmood A.M., Ameh J.M. In vitro antibacterial activity of Parkia biglobosa (Jacq.) root bark extract against some microorganisms associated with urinary tract infections. Afr. J. Biotechnol. 2007;6:1272-1275.

    Not in our library

  267. 267.

    Tamfu A.N., Roland N., Mfifen A.M., Kucukaydin S., Gaye M., Botezatu A.V., Duru M.E., Dinica R.M. Phenolic composition, antioxidant and enzyme inhibitory activities of Parkia biglobosa (Jacq.) Benth., Tithonia diversifolia (Hemsl) A. Gray, and Crossopteryx febrifuga (Afzel.) Benth. Arab. J. Chem. 2022;15:103675.

    Not in our library10.1016/j.arabjc.2021.103675

  268. 268.

    Saeidi S., Amini Boroujeni N., Ahmadi H., Hassanshahian M. Antibacterial Activity of Some Plant Extracts Against Extended- Spectrum Beta-Lactamase Producing Escherichia coli Isolates. Jundishapur. J. Microbiol. 2015;8:e15434.

    Not in our library10.5812/jjm.15434

  269. 269.

    Mina C.N., Farzaei M.H., Gholamreza A. Medicinal properties of Peganum harmala L. in traditional Iranian medicine and modern phytotherapy: A review. J. Tradit. Chin. Med. 2015;35:104-109.

    Not in our library10.1016/s0254-6272(15)30016-9

  270. 270.

    Friščić M., Jerković I., Marijanović Z., Dragović S., Hazler Pilepić K., Maleš Ž. Essential Oil Composition of Different Plant Parts from Croatian Petasites albus (L.) Gaertn. and Petasites hybridus (L.) G.Gaertn., B.Mey. & Scherb. (Asteraceae). Chem. Biodivers. 2019;16:e1800531.

    Not in our library10.1002/cbdv.201800531

  271. 271.

    Petrolini F.V., Lucarini R., de Souza M.G., Pires R.H., Cunha W.R., Martins C.H. Evaluation of the antibacterial potential of Petroselinum crispum and Rosmarinus officinalis against bacteria that cause urinary tract infections. Braz. J. Microbiol. 2013;44:829-834.

    Not in our library10.1590/s1517-83822013005000061

  272. 272.

    Tintino S.R., Souza C., Guedes G., Costa J., Duarte F.M., Chaves M., Silva V.A., Pessôa H., Lima M.A., Garcia C.A. Modulatory antimicrobial activity of piper arboreum extracts. Acta Bot. Croat. 2014;73:281-289.

    Not in our library10.2478/botcro-2013-0026

  273. 273.

    da Silva A.C.A., Matias E.F.F., Rocha J.E., Araújo A.C.J., de Freitas T.S., Campina F.F., Costa M.D.S., Silva L.E., Amaral W.D., Maia B., et al. Gas chromatography coupled to mass spectrometry (GC-MS) characterization and evaluation of antibacterial bioactivities of the essential oils from Piper arboreum Aubl., Piper aduncum L. e Piper gaudichaudianum Kunth. Z. Naturforsch. C J. Biosci. 2021;76:35-42.

    Not in our library10.1515/znc-2020-0045

  274. 274.

    Liao S.G., Zhang L.J., Sun F., Zhang J.J., Chen A.Y., Lan Y.Y., Li Y.J., Wang A.M., He X., Xiong Y., et al. Antibacterial and anti-inflammatory effects of extracts and fractions from Polygonum capitatum. J. Ethnopharmacol. 2011;134:1006-1009.

    Not in our library10.1016/j.jep.2011.01.050

  275. 275.

    Seifi M., Abbasalizadeh S., Mohammad-Alizadeh-Charandabi S., Khodaie L., Mirghafourvand M. The effect of Rosa (L. Rosa canina) on the incidence of urinary tract infection in the puerperium: A randomized placebo-controlled trial. Phytother. Res. 2018;32:76-83.

    Not in our library10.1002/ptr.5950

  276. 276.

    Peng M.M., Fang Y., Hu W., Huang Q. The pharmacological activities of Compound Salvia Plebeia Granules on treating urinary tract infection. J. Ethnopharmacol. 2010;129:59-63.

    Not in our library10.1016/j.jep.2010.02.029

  277. 277.

    Liang Y.-Y., Wan X.-H., Niu F.-J., Xie S.-M., Guo H., Yang Y.-Y., Guo L.-Y., Zhou C.-Z. Salvia plebeia R. Br.: An overview about its traditional uses, chemical constituents, pharmacology and modern applications. Biomed. Pharmacother. 2020;121:109589.

    Not in our library10.1016/j.biopha.2019.109589

  278. 278.

    Sittiwet C., Puangpronpitag D., Niamsa N. In vitro Antimicrobial Activity of Schefflera leucantha: The Potential of Respiratory Tract and Urinary Tract Infection Treatment. Int. J. Pharmacol. 2009;5:240-243.

    Not in our library10.3923/ijp.2009.240.243

  279. 279.

    Wang Y., Liang D., Khan F.-A., Zhang C.-L., Liu Y.-F., Chen R.-Y., Choudhary M.I., Yu D.-Q. Chemical constituents from Schefflera leucantha R.Vig. (Araliaceae). Biochem. Syst. Ecol. 2020;91:104076.

    Not in our library10.1016/j.bse.2020.104076

  280. 280.

    Karunai Raj M., Balachandran C., Duraipandiyan V., Agastian P., Ignacimuthu S. Antimicrobial activity of Ulopterol isolated from Toddalia asiatica (L.) Lam.: A traditional medicinal plant. J. Ethnopharmacol. 2012;140:161-165.

    Not in our library10.1016/j.jep.2012.01.005

  281. 281.

    Mao X., Guo H., Yao R., Bao L., Sun J., Bao Y., Guo B., Gao Y., Shi Y., Zhang H., et al. Crude polysaccharides from the seeds of Vaccaria segetalis prevent the urinary tract infection through the stimulation of kidney innate immunity. J. Ethnopharmacol. 2020;260:112578.

    Not in our library10.1016/j.jep.2020.112578

  282. 282.

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