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Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

Anjali Y. Bhagirath, Yanqi Li, Rakesh Patidar and 4 more

International Journal of Molecular Sciences · 2019 · Review · CC BY

doi:10.3390/ijms20071781

Abstract

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets.

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

1Antimicrobial resistance in several infectious pathogens has become a serious public health concern. As per the World Health Organization (WHO), the 21st century may well be called the post-antibiotic era. The incidence of infections caused by multidrug-resistant (MDR) gram-negative bacteria is increasing worldwide. The emergence of pan-drug-resistant (PDR) bacteria, which are resistant to all classes of available antimicrobial agents, represents a worrisome endpoint in the fight with bacterial infections. Despite the limited reports of isolation of such resistant bacteria, there is a great concern in the medical community, as clinicians are left with very few options for treating patients with PDR bacteria.

2Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae are well-known nosocomial pathogens; recent years have seen a worldwide rise in their multi-drug resistant and pan-drug resistant counterparts. They have been included in the WHO’s list of antibiotic-resistant priority 1 (critical) pathogens. They have also been annotated as being a part of the ESKAPE pathogen group (Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacteriaceae). This acronym is derived from their ability to “escape” from antimicrobial therapy. This acronym has been further modified as ESCAPE pathogens with the ‘C’ referring to Clostridium difficile, and ‘E’ for all Enterobacteriaceae, including E. coli, Proteus spp., and Enterobacter spp.. Studies have documented increasing resistance rates in P. aeruginosa clinical isolates to fluoroquinolones, cephalosporins, and carbapenems. A. baumannii and K. pneumoniae are now being recognized as emerging pathogens in many medical facilities. According to the National Nosocomial Infections Surveillance (NNIS) data, the proportion of infections due to Acinetobacter spp. has been steadily increasing, and now accounts for ∽7% of intensive care unit (ICU)-related pneumonias. Infections due to multidrug-resistant A. baumannii have been associated with increased lengths of hospital and ICU stays. K. pneumoniae is also a well-recognized nosocomial pathogen, and an important cause of pneumonia and urinary tract infections in ICU settings. Since the early 1990s, many reports of extended-spectrum β-lactamase (ESBL)-possessing K. pneumoniae have emerged. In surveillance studies, resistance to third-generation cephalosporins amongst K. pneumoniae has reached ∼15–20%, and ciprofloxacin resistance has ranged from ∼10–50%. Recently, outbreaks of carbapenemase-producing K. pneumoniae have been reported, threatening the use of this class of antimicrobial agents.

3Even though resistance mechanisms in these organisms have been increasingly explored, limited information is available regarding the role of their sensory mechanisms in resistance. Sensing is the first step for bacterial defense against extrinsic environmental stressors such as antibiotic exposure and potentially plays a role in the evolution of resistance mechanisms. Two-component regulatory systems (TCSs) in bacteria act as key sensory pathways that enable microbes’ adaptation in both the environment as well as the host. Studies have suggested that TCSs may play an important role in the survival and development of antimicrobial resistance. This review aims to explore the connection between TCSs and antimicrobial resistance in pathogenic gram-negative bacteria. We will focus on three key bacteria: P. aeruginosa, K. pneumonia, and A. baumannii, which pose serious threats to human health. We believe these organisms also share a commonality in terms of the mechanism of antibiotic resistance.

2. Antimicrobial Resistance in Gram-Negative Pathogenic Bacteria

4The development and emergence of antimicrobial resistance is a complicated process and yet occur soon after the introduction of novel anti-microbial drugs. Resistance to antibiotics can develop either by spontaneous mutations or by the acquisition of resistant genes. The origin of antibiotic-resistant genes may be present on commensal or environmental bacteria. To fully understand the acquisition and spread of antibiotic resistance among the human bacterial pathogens, these ecosystems should be taken into consideration.

5Development of resistance is thought to be an ongoing evolutionary process. A genetic change in the form of mutation often occurs naturally. Such mutations can influence the ability of a cell to grow and survive in the presence of environmental stressors such as antimicrobials. The selection of mutant is dependent on the intensity of selective pressure, the immune status of the host, the size of the pathogen population, the presence of other microorganisms and lastly the geographical topography. Often, random mutations of the genes encoding for the antibiotic lytic enzymes give rise to modified catalysts with increasingly extended spectra of resistance. One example is the β-lactamase encoding gene. The β-lactamase encoding genes are ancient and have been isolated in strains from remote environments. The plasmid-encoded β-lactamase, TEM, has been shown to be related to a variety of enzyme families, providing hints to its adaptability.

6Antimicrobial resistance can develop through several mechanisms. These can be broadly categorized into two main types; intrinsic and acquired. Intrinsic resistance mechanisms include inherent bacterial defenses such as altered outer membrane permeability and hyperactive efflux pumps; whereas, the acquired resistance mechanisms involve horizontal gene transfer and acquisition of genetic elements. Here we will discuss these mechanisms with respect to P. aeruginosa, K. pneumonia, and A. baumannii. Figure 1 highlights the key resistance mechanisms in pathogenic bacteria.

2.1. Intrinsic Resistance

7Intrinsic gene functions leading to naturally resistant phenotypes have given rise to the term ‘resistome’. Resistome of a microorganism includes all the genes and their products that contribute to its antibiotic resistance. Understanding the resistome is critical as it forms the basis for horizontal gene transfer and the eventual emergence of antimicrobial resistance. The search of P. aeruginosa PAO1 genome, for example, reveals several genes encoding enzymes for resistance to chloramphenicol, aminoglycoside, and β-lactam antibiotics. Resistome analysis in multidrug-resistant isolates of K. pneumoniae revealed an average of 11–13 acquired resistance genes along with the extended-spectrum beta-lactamase genes and the AraC-type regulator, which confers resistance to virtually all antimicrobial agents available in clinical practice. The genome of A. baumannii encodes a variety of different β-lactamases, including metallo-enzymes that confers resistance to carbapenems, as well as resistance-nodulation-cell division (RND)-type multidrug efflux pumps (AdeABC, AdeFGH, and AdeIJK).

8The outer membrane (OM) in gram-negative bacteria plays a major role in pathogen-host interaction and forms a selective permeability barrier. OMs, like other biological membranes, are fundamentally built as a bilayer of lipids. As such, lipid bilayers permit little permeability for hydrophilic solutes, including most nutrients and many antibiotics. They contain protein-formed channels, allowing the influx of nutrients and the extrusion of waste products. Porins are one such class of constitutively expressed nonspecific or substrate specific diffusion channel-forming proteins. The properties of these porins are significant for the intrinsic level of antibiotic resistance in gram-negative bacteria. The major outer membrane porin of P. aeruginosa (OprF) transports solutes at least two times slower compared with that of bacteria, such as E. coli. A recent study in K. pneumoniae suggested that porin deficiency is a widespread phenomenon in MDR resistant isolates. The genome of K. pneumoniae encodes for several key porins, however, OmpK35, OmpK36, and OmpK37 are most widely associated with AMR. Most susceptible clinical isolates of K. pneumoniae express both OmpK35 and OmpK36 porins, while most extended spectrum β-lactamases encoding K. pneumoniae express only the OmpK36 or none. Very often loss of one type of porin is compensated by expression of others, adding to the already complex role of porins in antimicrobial resistance. The major A. baumannii porin, OmpA, has been shown to play a crucial role in AMR. OmpA facilitates AMR by extrusion of antibiotics from the periplasmic space through the outer membrane and by interacting with inner membrane efflux systems facilitating surface motility and biofilm formation.

9Bacterial efflux pumps represent another important mechanism for limiting antibacterial molecules inside the cell or from their targets. Efflux pumps are central to the adaptation and survival of the cell in various environments. These are divided into families such as the RND; major facilitator superfamily (MFS); small multidrug resistance (SMR), and multidrug and toxin extrusion (MATE) family of proteins. Another class of proteins, known as the ATP binding cassette (ABC) transporters, have been found to be present in various pathogenic bacteria and have been shown to be involved in antibiotic resistance. Contribution of efflux systems to clinically important antibiotic resistance has been described in P. aeruginosa (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM), A. baumannii (AdeABC, AdeFGH, CraA, AmvA, AbeM, and AbeS), and K. pneumoniae (TolC, AcrAB, KocC, and KexD). Readers are referred to excellent reviews by Yoon et al. Pulzova et al., and Zowalaty et al..

2.2. Acquired Resistance

10Modifying enzymes catalyze reactions including acetylation, phosphorylation, and adenylation. The steric hindrance caused decreases the affinity of the drug for its target, resulting in AMR. One example is aminoglycoside acetyltransferase (AAC) found in Pseudomonas and Acinetobacter which can inactivate most aminoglycosides including amikacin and gentamicin. These enzymes are either acquired through horizontal transfer of plasmids or transposons or through spontaneous mutations which expand the functionality of encoding genes. The other mechanisms are target modification and lipopolysaccharides (LPSs) modification. Where antibiotics affect bacterial cell-wall or target cell division, target modification works by either acquisition of binding proteins that do not affect cell-wall or acquisition of mutations within the RNA polymerase, DNA gyrase or topoisomerase IV, modification of ribosomal proteins, or protection of the target site by another protein altogether.

11The other more complex mechanism for evading external stressors such as antimicrobials is the formation of structured communities known as biofilms. Biofilms are comprised of an exopolysaccharide matrix surrounding the bacterial communities, with well-established channels for nutrients and water inflow as well as waste outflow. The exopolysaccharide matrix limits the penetration of antibiotics while the proximity allows for horizontal gene transfer from the persister cells. Persister cells are those subgroups that have survived an antimicrobial exposure and can give rise to resistant colonies. Further, cells inside the biofilms grow relatively slowly and present low metabolic activity which is detrimental to the activity of most currently available antibiotics. Interestingly, sub-inhibitory concentrations of aminoglycosides, especially tobramycin, have been shown to induce biofilm formation in P. aeruginosa. Azithromycin has been shown to inhibit the expression of the small RNAs rsmY and rsmZ, a process that depends on the GacA/Rsm signal transduction pathway. GacA/Rsm pathway is known to positively control quorum sensing and reciprocally control biofilm formation in P. aeruginosa. Readers are referred to reviews by Høiby et al. 2010, Philip S. Stewart, 2002, and Ahmed et al. 2018.

12Comparative genomic analysis suggests that horizontal gene transfer (HGT) plays a significant role in determining the genetic repertoire of the clinical isolates of pathogenic bacteria. Genomic diversity is, in part, attributable to the acquisition of genetic material that has integrated into the chromosome at a relatively limited number of sites. Acquired mobile genetic elements (plasmids, insertion sequences, transposons) mobilize the antimicrobial resistance genes and can confer resistance to the major classes of antimicrobials among different bacteria. Resistance to environmental stressors is triggered by contact between bacterial sensing systems and the immediate extrinsic environment. The interaction between the sensing systems within the bacteria and the external environment leads to adaptive physiological changes through modulation of gene expression. Two-component regulatory systems detect physical and chemical changes in the environment and then relay this signal to the cytoplasm, where the modulation of gene expression occurs.

3. Two-Component Regulatory Systems in Gram-Negative Pathogenic Bacteria

13TCSs have been known to regulate a wide variety of cellular functions in response to environmental signals such as nutrient limitation, oxygen availability, phosphate limitation or osmolarity, and antimicrobial agents. For instance, in P. aeruginosa PilG/PilH mediates pili production under yet unknown signals and NarX/NarL is involved in nitrate sensing and respiration, biofilm formation and motility. AlgZ/AlgR mediates alginate production under osmolarity and nitrate signals in mucoid strains. PhoR/PhoB senses inorganic phosphate and is involved in regulating quorum sensing and swarming motility. PfeS/PfeR senses enterobactin mediated iron acquisition while FleS/FleR mediates adhesion and sense mucins. GacS/GacA controls virulence in response to unknown signals and CbrA/CbrB senses various carbon sources and modulates metabolism, virulence and antibiotic resistance. CheA/CheY regulates chemotaxis in response to magnesium.

14Typically, a TCS consists of a sensor kinase with a conserved histidine residue [H box] also known as histidine kinase [HK] which senses external signals and transfers a phosphate molecule to the response regulator [RR] with a conserved aspartate residue which then mediates cellular response towards the external stimuli (Figure 2). In contrast to the orthodox TCS systems, the phosphorelay system mediated by hybrid histidine kinase (HHK) is also shown.

15Bacterial HKs are classified into five types (Type I, II, III, IV, and CheA). Among the five HK family types, Type I and II are found to be genetically related, but type III and IV are not. The likeness between Type I and II is based on the presence of orthodox kinase domains, which contain the N, G1, F, and G2 consensus motifs. Type III and IV HKs possess so-called unorthodox kinase domains in which N1 of the N-box motif is either a glycine (Type III) or a proline (Type IV) residue, the F box is absent, and the G2 motif is truncated. Within the Type I group, three separate subtypes exist: The Type IA group contains 12 HKs, the Type IB group contains the hybrid HKs and the Type IC group contains three HKs, including the nitrogen regulator ntrB. The kinase domain of CheA is characterized by insertions between the N and G1 boxes and the G1 and F boxes. The N-box of CheA contains a histidine residue at the N1 position. Secondary structure analysis of HKs predicts a helix–loop–helix structure important for signal recognition.

16The HK types found in P. aeruginosa genome were assembled in Figure 3 using the gene tables of the completed genomes listed in the Pseudomonas genome database (http://www.pseudomonas.com). This was compared with the available classification on MiST3 (mistdb.com). The protein sequences were aligned in Phylogeny.fr using MUSCLE for multiple alignments, PhyML for tree building, and TreeDyn for tree rendering. Of the total HKs identified in P. aeruginosa, one cluster within the Type IA group (PA1396, 1976, 1992, 3271, and 4936) contains orthodox kinase domains while the H-box motifs containing a non-polar residue at position 4 and a glutamine residue at position 5. This clade of HKs forms a distinct branch within the Type IA group. In addition, a cluster of HKs in the Type IC group possesses the consensus H-box motif HDLNQPL in which the asparagine residue replaces the typical positively charged residue at position 4, but the glutamine residue at position 5 is highly conserved. P. aeruginosa lacks Type II HKs and possesses four CheAs. Two HKs, PA3078, and PA4380, which cannot be assigned to the defined type, are categorized as unclassified. Helix–loop–helix structures are also predicted in the H-box region of the Type III HKs. The H to N distances for each of the HK types are similar to those found in the different HK types of E. coli. Finally, the majority of the HKs are found in operons with cognate RRs.

17Apart from the classical HK and RR domains, a histidine phosphotransfer protein (Hpt) may be encoded in the same operon. These Hpt proteins are sometimes present either as isolates, as seen in orphan histidine kinase, or along with HHK for phosphotransfer. The division of domains in phosphorelays provides additional checkpoints for phosphorylation and may serve to integrate signals for a collective response as cross-talks are allowed in such systems. Recent studies also suggest a non-phosphotransfer based signaling pathway (Figure 4), in which two HKs can interact directly to elicit a certain response by controlling downstream responses of the non-cognate binding partners.

3.1. One-Component Signaling Systems

18One-component systems (OCSs) can be defined as proteins that contain both input and output domains but lack typical histidine kinase and response regulator domains of TCSs. OCSs represent the simplest model for signal transduction by a single protein. One example is RocR in which PAS and HTH are input and output domains respectively. As reported by Ulrich et al., one-component systems were shown to numerically dominate over TCSs in bacteria which was also co-relatable to their genome size. One component signal transduction proteins also demonstrate less conservation within their input and output domain architecture than TCSs. Based on domain architecture, one component systems seem to be the precursors for two-component signaling systems. The structure and abundance of TCSs also suggest that the addition of a histidine kinase might have been an evolutionary step at intercepting external signals.

19P. aeruginosa PAO1 (genome size 6.2Mbp) encodes for 435 OCSs (mistdb.com) and 130 TCSs (41 HK; 17 HHK; 69 RR; others 5). This is not very different from clinical strains P. aeruginosa 138,244 (widely disseminated and associated with multidrug resistance) (428 OCSs and 134 TCSs), P. aeruginosa 152,504 (rare allele) (466 OCSs, and 145TCSs). However, in contrast, K. pneumonia subsp. pneumoniae strain HS11286 (genome 5.3Mbp) encodes for 387 OCSs and 66 TCSs (27 HK; 5 HHK; 32 RR; Others 2), and A. baumannii (genome 4.3 Mbp) exhibits 235 OCSs and 29 TCSs (11 HK; 3 HHK; 15 RR).In contrast to the one-component systems, the counterparts of two-component signaling systems are highly conserved, and the RRs are more conserved than HKs.

3.2. Hybrid Histidine Kinase [HHK] and Direct-Interaction-Mediated Signaling

20Hybrid histidine kinase proteins have, in recent years, become an emerging group of proteins with demonstrated roles in complex signaling mechanisms. P. aeruginosa PAO1 encodes for 15 HHKs while its environmental counterpart P. aeruginosa UCBPP-PA14 has 18. K. pneumoniae subsp. pneumoniae HS11286 encodes for 5 and A. baumannii encodes for 3 HHKs in their respective genomes. HHKs in P. aeruginosa PAO1 includes those involved in a key regulatory pathway regulating biofilm formation and virulence (RetS; GacS; LadS; PA1611). HHKs in K. pneumoniae include the ArcB (oxygen sensor); EvgS (capsular polysaccharide); BarA (carbon metabolism); RcsC (motility and capsular synthesis); however, those in A. baumanii (IX87_RS17040, IX87_RS13225, IX87_RS03185) remain largely unexamined. Interestingly, HHKs have been shown to function via both canonical phosphotransfer-mediated signaling as well as by direct protein–protein interaction-mediated signaling one example is the LadS-GacS-RetS-PA1611 system in P. aeruginosa. Previously, this mechanism has been observed in the PmrB/PmrA TCS in Salmonella. The PmrB/A TCS is required for resistance to acidic environment and antibiotic stresses. PmrD, another regulatory protein from the same operon, binds to and protects the phosphorylated form of PmrA from the phosphatase activity of its cognate sensor, PmrB.

21In the phosphorelay systems involving HHKs, the Hpt protein serves as the phosphodonor to the terminal response regulator which eventually mediates a cellular response via the output domain. The Hpt protein is also capable of receiving phosphor from HHKs and functioning as an independent protein. An Hpt may serve as a point of signal integration or transmission of signals between two non-cognate TCSs. Although as much as 90% of the TCSs in eukaryotes use hybrid HKs, only 20% of the characterized prokaryote genomes encode hybrid kinases whereas in archaea the number is only 1%. This is explained by the fact that the larger size of a eukaryotic cell necessitates complex signaling and multi-step phosphorelays. With the modular organization in the phosphorelays, phosphorylation at any level may lead to activation of the output domain.

22Recent studies have highlighted interactions between the HHKs and other auxiliary proteins such as those involved in biofilm formation and regulating efflux pumps in pathogenic bacteria. One classic example is the SagS HHK in P. aeruginosa. SagS is expressed during the biofilm development stages and regulates c-di-GMP levels as well as activates MexAB-oprM and MexEF-oprN systems.

23As signaling pathways must act in a combinatorial fashion for normal cellular functioning, there is a possibility of inter-signaling system- information transfer. The direct interaction between TCS proteins is a recently uncovered strategy that the bacteria use to integrate signals other than those detected by a given sensor. These proteins may function as negative or positive regulators of the TCSs involved. Regulatory proteins may also target the response regulators to either protect from dephosphorylation or cause dephosphorylation. Apart from pure phosphotransfer-based signaling, some sensor kinases may also function by either de-phosphorylating the response regulator or protecting the RR from de-phosphorylation. They can perform these functions by binding or sequestering their cognate/non-cognate partners.

24Interestingly, more and more reports have emerged suggesting that TCS–TCS direct interaction may also affect signaling states and act as signal transducers for interacting proteins. A clear correlation between structural properties, domain interaction, and signaling states is suggested. Though a single TCS may function independently in several different ways, the interaction between TCSs can be described with Boolean operators with the analogy to the neural networks as was first noted in E. coli. In E. coli, ArcB, TorS, RcS, and EvgA have been shown to signal through RRs in non-cognate clusters. These recruitment mechanisms are crucial for chemotaxis and sporulation systems. In such case, HHKs are a particularly interesting group, which are able to function alone or in conjunction with diverse cognate and non-cognate partners to form signaling complexes. A multilayer regulation provides an organism greater control over environmental responses. For cells to function as one single unit, the signaling pathways must act in a combinatorial fashion. Thus, apart from sensing the external signal, there is a possibility of inter-signaling system-information transfer, with HHKs being involved in forming signaling complexes and play a role in multidrug resistance.

4. Role of Two-Component Regulatory Systems in Antimicrobial Resistance in Gram- Negative Pathogenic Bacteria

25The current knowledge on bacterial genome sequences has made it possible to investigate, identify, and predict two-component regulatory proteins as well as their interacting partners. Two-component regulatory proteins in P. aeruginosa have been widely studied and reviewed. However, the same is not the case for K. pneumoniae and A. baumannii. Table 1 provides a comprehensive listing of available knowledge about various two-component regulatory systems in these three pathogens.

26We analyzed two-component regulatory proteins between these three pathogens and found a surprising conservation in the PmrAB, GacSA, AdeRS, and BaeSR, systems. Among the HKs and RRs, we observed a greater degree of conservation in the RRs. We will discuss the available pool of knowledge on these four systems and their role in antimicrobial resistance (Figure 5). We focus only on these four TCSs as they exist across the three bacteria under discussion and are related to antimicrobial resistance.

4.1. The PmrAB System

27PmrAB TCS was shown to be involved in the LPS modification in P. aeruginosa. The genes pmrB and pmrA encode for the sensor histidine kinase (PmrB) and its cognate response regulator (PmrA), which, once phosphorylated, activates the pmrC and pmrHFIJKLM as well as downstream genes. Genetic targets of PmrAB in P. aeruginosa include the cprA gene required for polymyxin resistance and the pmr genes (PA3552–PA3559) for resistance from antimicrobial peptides. The HK PmrB in P. aeruginosa, K. pneumonia, and A. baumanii showed a BLOSUM similarity score of 29%. PmrA in P. aeruginosa, K. pneumonia, and A. baumanii showed a 43% similarity (BLOSUM). Phylogenetically, PmrA in P. aeruginosa is more closely related to K. pneumoniae as compared to that of A. baumanii. Interestingly, a closer look at the past studies reveals a far more functional similarity.

28Mutations in the pmrAB operon (polymyxin resistance) have been linked to enhanced resistance to antimicrobial peptides as well as survival in chronic infections. The PmrAB system (PA4776–PA4777) was first identified in P. aeruginosa clinical isolates with resistance to polymyxins. It was observed that a mutation in the PmrAB locus resulted in resistance to polymyxins and other cationic antimicrobial peptides (CAPs). Further PmrAB was shown to have a role in survival and persistence in chronic lung infections. A mutation in the PmrB resulted in an increased ability to survive in a mouse model of chronic respiratory infection as compared to both the wild type as well as those adapted to the mouse lung but lacking the mutation. Recent studies have argued that PmrB mutants were, in fact, more susceptible to antimicrobials, such as ciprofloxacin, colistin, gentamycin, polymyxin B, tobramycin, and tetracycline. The same study also identified at least 216 proteins that were differentially regulated in a PmrB mutant. Interestingly, the PmrB mutant was found to show enhanced resistance to host-derived antimicrobial peptides.

29To survive environmental stressors, one of the unique mechanisms that the pathogenic bacteria employ is the ability to remodel their outer membranes. This remodeling occurs, mainly at the level of lipid A in the lipopolysaccharide (LPS). The remodeling of lipid A occurs in a PhoPQ-PmrAB dependent manner by palmitoylation or deacylation, or both, by the addition of 4-aminoarabinose (L-Ara4N) or phosphoethanolamine (pEtN). The addition of L-Ara4N is considered the most effective by decreasing the net negative charge of the membrane to zero. Thus, this would reduce its binding to polymyxins, resulting in resistance. The second, PEtN modification, decreases the net charge from −1.5 to −1.

30Similar to that in P. aeruginosa, pmrAB TCS in K. pneumoniae has been shown to regulate lipopolysaccharide modification. In A. baumanii, mutations in PmrAB have been shown to be associated with colistin resistance, however, the mechanism is still unclear. It has been suggested that mutations in PmrA or B, or both, could result in lipid modifications. The HK gene pmrB seems to be the more common site for bacterial mutations compared to the RR gene pmrA. Interestingly, the acquisition of colistin resistance was also found to be associated with decreased virulence and fitness. In contrast, recent studies on PmrB mutant in A. baumanii have shown no reduction in virulence or fitness. It has been suggested that PmrB senses acidic pH (pH 5.5), low magnesium levels and iron limitation, and also increases the survival under antimicrobial stress via yet unknown mechanisms.

4.2. The GacSA System

31The GacSA TCS is one of the most widely studied systems in P. aeruginosa. GacS is an HK and GacA is the RR. Phosphorylation of GacS is under the control of hybrid sensor kinases, RetS (PA4856), PA1611, and LadS (PA3974). These three HHKs are known to bind to GacS under yet unknown environmental stimuli to reciprocally control the acute-chronic disease transition in P. aeruginosa. Once phosphorylated, GacA activates the transcription of two small regulatory RNAs, RsmZ (PA3621.1), and RsmY (PA0527.1). RsmY/Z control the activation of the RNA-binding protein RsmA (PA0905). RsmA is known to regulate genes of the Type III secretion system, type IV pili formation and iron homeostasis while repressing QS, Type VI secretion and potentially other transcription factors. The MexEF-OprN pump in P. aeruginosa has been found to remove several antibiotics, Pseudomonas quinolone signal and specific quorum sensing molecules from the cell. RsmA has been shown to control the expression of the MexEF-OprN pump. A rsmA mutant demonstrated results in activated expression of the genes encoding the MexEF-OprN pump. The GacSA system is also involved in antibiotic resistance, through RsmA/RsmZ, to three different families of antibiotics: tobramycin, ciprofloxacin, and tetracycline. Further, biofilms known to be resistant to available antibiotics in P. aeruginosa are affected primarily by the pel and psl operons and broadly by the modulation in intracellular c-di-GMP levels. c-di-GMP is a second messenger shown to promote biofilm formation and antimicrobial resistance in P. aeruginosa. Both the pel and psl operons are post-transcriptionally regulated by the RetS-LadS systems via RsmY/Z. c-di-GMP exerts a broader control via its effect on a variety of regulatory proteins and RNAs. Previously, it has been shown that c-di-GMP levels, are modulated by the diguanylate cyclase WspR (PA3702), which is involved in the switch between acute and chronic infection phase and is shown to be dependent on RsmY/Z. Small colony variants (SCV) of P. aeruginosa clinical isolates are known to exhibit hyper biofilm formation, hyper pilation and demonstrate enhanced resistance to several antibiotics. Often the SCV phenotype is associated with elevated intracellular levels of c-di-GMP. Studies have also shown that a mutation in the PmrAB system is associated with SCVs and hyperbiofilm phenotypes.

32The amgRS operon encodes a membrane stress-responsive TCS found to be linked to intrinsic aminoglycoside resistance in P. aeruginosa. The AmgS is the sensor kinase and the AmgR is the response regulator. AmgRS TCS has been shown to provide resistance against aminoglycoside-related membrane damage. AmgRS was shown to be activated in the presence of aminoglycosides which in turn promoted the mexXY expression. It was observed that while overexpression of the AmgRS system slightly reduced the colony size of wild-type PA14, the SCV formation was enhanced significantly when GacA was overexpressed simultaneously,.

33Similar to P. aeruginosa, the GacSA system in A. baumannii was shown to be a global regulator of virulence, pili, biofilm formation and resistance to host-derived antimicrobial peptides and motility. It was also shown that GacSA played a key role in attachment to abiotic surfaces, arginine metabolism, and biofilm formation. A GasS mutant of A. baumannii showed decreased virulence towards Candida albicans and was unable to use citrate as the carbon source. The phenylacetic acid (PAA) pathway is crucial to the metabolism of aromatic compounds and environmental pollutants in bacteria. In A. baumanii, the PAA pathway is encoded by the paa operon and it was observed that the deletion of gacS resulted in repression of the entire paa operon.

34A search for the GacSA system in K. pneumoniae identified BarA with 93% similarity to the GacS HK and UvrY with 100% similarity to the GacA RR in P. aeruginosa. BarA and UvrY correspond to KpST66_3517 and KpST66_0986 in K. pneumoniae genome. These proteins consist of an N-terminal cytosolic domain, a canonical pair of transmembrane regions linked by a periplasmic bridge, a transmitter domain containing a conserved histidine residue, a central receiver domain with a conserved aspartate residue, and a C-terminal phosphotransfer domain with a conserved histidine residue. To date, there have been few studies on this TCS and its role in antimicrobial resistance in K. pneumoniae.

35The carbon storage regulation (Csr) system has been shown to have a major impact on regulation of carbon metabolism pathways, motility, and biofilm formation. The Csr system is composed of small regulatory RNAs possessing repeated sequence elements that allow them to interact with multiple copies of the RNA binding proteins, thereby preventing its regulatory interaction with its mRNA targets downstream. UvrY has been shown to activate the expression of the noncoding csrB and csrC RNAs in E. coli. This, in turn, sequesters CsrA and prevents it from activating downstream genes. CsrB is a carbon source utilization system which has been shown to integrate signals from the UvrY-BarA TCS. Functional studies for the UvrY-BarA in Escherichia coli have shown roles in catalase expression, biofilm formation and quorum sensing.

36Unlike PmrAB, AdeRS, and BaeSR, GacSA is not a contiguous operon in any of the three pathogens discussed above suggesting that GacSA may be involved in crosstalk between different TCSs. The full extent of its role in these pathogens yet remains to be understood.

4.3. The AdeRS and the BaeSR Systems

37The AdeRS two-component regulatory system is composed of the AdeS as a sensor kinase, whereas AdeR is the RR. The AdeRS system is one of the best characterized TCS in A. baumanii. The AdeRS TCS has been shown to be involved in a more global regulation of gene expression in A. baumanii either directly in sensing cell density/growth, or indirectly as in sensing osmolality via the BaeSR system.

38Efflux pumps are usually regulated by regulatory proteins adjacent to them. There are few reports of efflux pumps regulated by TCSs including the NorA pump in S. aureus. Interestingly, AdeRS has been demonstrated to control the expression of adeABC efflux pump in A. baumanii. AdeABC efflux pump, a three-component system, and a member of the RND family has been shown to play a role in resistance to aminoglycosides, tetracycline, erythromycin, chloramphenicol, trimethoprim, fluoroquinolones, and tigecycline. AdeABC consists of AdeA, the inner membrane fusion protein, AdeB the transmembrane component, and AdeC the outer membrane protein. A. baumanii ATCC 17978 has two adeA genes and one adeB gene, but lacks the adeC. The overexpression of AdeABC is also associated with increased virulence, which probably explains why adeRS mutations are frequently observed in clinical isolates. Recent studies showed that AdeRS, directly or indirectly, regulates 579 genes, most notably those involved in the expression of efflux pumps, biofilm formation and virulence in a Galleria mellonella larvae infection model. Intriguingly, some outcomes of the AdeRS deletion appeared to be strain specific. Further truncations or point mutations within AdeR or S leads to activation of AdeABC efflux system and results in multidrug resistance.

39A search for AdeR homolog in P. aeruginosa resulted in a yet unknown response regulator belonging to OmpR family, containing a DNA-binding response regulator with 91% similarity (WP_033958295.1) and 93% similarity in K. pneumonia (WP_004199992.1). The roles of either are not known yet.

40The BaeSR TCS was first discovered in E. coli and Salmonella enterica serovar Typhimurium. The BaeSR TCS consists of an inner-membrane-bound BaeS HK, and a cytoplasmic RR, BaeR. Genome analysis of A. baumannii ATCC 17978 shows that the coding sequences of baeR (A1S_2883) and baeS (A1S_2884) are arranged sequentially, suggesting that the two genes may be co-transcribed as one operon. P. aeruginosa encodes a similar protein to BaeS (Locus: CRQ12647; 96% similarity), whose function remains unknown. Deletion of baeSR in A. baumanii led to a significantly reduced expression of the major efflux pumps, such as AdeABC, AdeIJK, and MacAB-TolC, resulting in increased susceptibility to tigecycline. The regulons of AdeRS and BaeSR overlap. This could also mean that BaeSR may function through crosstalk with AdeRS.

5. Two-Component Regulatory Systems as Potential Drug Targets

41Two-component regulatory systems in gram-negative pathogens, though highly complex, may serve as attractive drug targets for a variety of reasons. The first reason is the high degree of structural and functional homology between various TCSs. A compound that is effective against a specific TCS, should plausibly be effective against other bacteria too,. Secondly, TCSs regulate diverse, but essential functions in the cells and thus form a very effective target so that an inhibitor would inflict a global effect and not just targeting one pathway. Targeting a central regulatory system can significantly affect cell viability with low risk of development of quick resistance. Thirdly, many antimicrobial resistant genes are regulated either directly or indirectly by TCSs and targeting TCSs forms an excellent adjunct to currently available antimicrobials. Lastly, the possibility of negative side effects with the use of TCS targeting drugs are expected to be minimum as the bacterial histidine based TCS is very different from the eukaryotic serine/threonine based signaling systems. Thus, TCSs serve as an excellent target for drug development for combating microbial infections, including those resistant to currently available antibiotics.

42Designing a drug-targeting specific TCSs is, however, complicated. The possible sites of intervention for a TCS are to be determined. Studies in the past have targeted the RR DNA binding, autophosphorylation sites as well as ATP-binding domains. Suggested sites for targeting include the site for autophosphorylation, site of interaction for HK-RR, facilitating the dephosphorylation of the HK, and inhibiting binding to the downstream genes. The question remains about the active sites for the known TCSs and whether they are common to all pathogens of one class. Targeting TCSs could be better if the targeted TCSs were conserved across several gram-positive and gram-negative bacterial species. Then there is the question about selectivity and spectrum of activity based on conservation of the active sites. Undoubtedly, further studies are needed before an antimicrobial drug targeting TCS is successfully developed.

6. Conclusions and Perspective

43Studies of TCS signaling circuits continue to reveal new layers of complexity for these systems. The conventional notion of the TCSs is frequently being challenged by new findings and our understanding of bacterial signaling through TCSs and other related systems is continuously evolving. The complex connection of bacterial signaling systems and antibiotic resistance are expected to be revealed by further studies and so will the underlying mechanisms.

44Autoregulation is an important concept in TCS signaling and has only recently begun to emerge and is well-illustrated by the BvgS system from the BvgS/BvgA system in Bordetella bronchiseptica. It was observed that autoregulation by BvgS modulates the sensitivity of the system to an applied stimulus. Autoregulation can be positive or negative. Positive autoregulation occurs when a response regulator activates transcription of its own gene and the gene encoding its partner histidine kinase. In contrast, negative autoregulation is less common and involves a response regulator that represses its own expression. The other example of autoregulation within TCSs is the PhoQ/PhoP system in E. coli. In the steady state, output was unaffected by autoregulation over a wide range of (stimulus levels) magnesium concentrations. However, when faced with growth-limiting levels of magnesium, the autoregulation of histidine kinase, PhoQ amplified the output. When PhoQ was mutated to incapacitate phosphatase activity, there was strong amplification of autoregulation irrespective of the stimulus conditions. Phosphorylation, though important, is not necessary for autoregulation. In the case of TorR and LuxO, the response regulator can repress its own expression, irrespective of its phosphorylation status. Interestingly, autoregulation has also been said to result in a “short term memory” or a “learning behavior.” This means that once a signal has been perceived in the past, the bacteria form a memory of the stimulus and upon subsequent exposures respond faster or more extensively to a signal. In the case where two proteins “cross-communicate” through the expression of an auxiliary protein, also known as two-component “connectors,” autoregulation may influence the system by controlling the relative concentrations of the interacting proteins. Understanding autoregulation is important because often it is mediated by highly conserved proteins and can be acquired by HGT. This is important to developing antimicrobial resistance amongst pathogens and must be considered when identifying viable drug targets.

45Cross-talks of the TCSs and information exchange through direct interactions are other intriguing aspects of bacterial signaling mediated by TCSs and related systems. Is there a possibility of physiological cross-talk amongst TCSs in different species given their similarities in domains and functions? Further work is required in P. aeruginosa, A. baumanii, and K. pneumoniae to investigate the role of autoregulation, identify connectors in cross-talk of the TCSs, and its role in antimicrobial resistance. In this increasingly critical time of drug resistance, there is a growing need to understand the signals perceived by TCSs, their complex circuitries, as well as their modular architectures. New methods are to be developed to study TCS activity in vivo to answer questions about specificity and selectivity. In any case, TCSs promise a significant therapeutic target.

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Dissemination of Antimicrobial Resistance in Microbial Ecosystems through Horizontal Gene Transfer · 2016
No notice
81.
Otto M. Bacterial sensing of antimicrobial peptides. Contrib. Microbiol. Immunol. 2009;16:136-149.
Not in our library10.1159/000219377
82.
Rodrigue A., Quentin Y., Lazdunski A., Méjean V., Foglino M. Cell signalling by oligosaccharides. Two-component systems in Pseudomonas aeruginosa: Why so many? Curr. Trends Microbiol. 2000;8:498-504.
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83.
Ma S., Wozniak D., Ohman D. Identification of the histidine protein kinase KinB in Pseudomonas aeruginosa and its phosphorylation of the alginate regulator algB. J. Biol. Chem. 1997;272:17952-17960.
Not in our library10.1074/jbc.272.29.17952
84.
Benkert B., Quack N., Schreiber K., Jaensch L., Jahn D., Schobert M. Nitrate-responsive NarX-NarL represses arginine-mediated induction of the Pseudomonas aeruginosa arginine fermentation arcDABC operon. Microbiolgy (Reading, England). 2008;154:3053-3060.
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85.
Kimbara K., Chakrabarty A.M. Control of alginate synthesis in Pseudomonas aeruginosa: Regulation of the algR1 gene. Biochem. Biophys. Res. Commun. 1989;164:601-608.
Not in our library10.1016/0006-291x(89)91502-7
86.
Bielecki P., Jensen V., Schulze W., Godeke J., Strehmel J., Eckweiler D., Nicolai T., Bielecka A., Wille T., Gerlach R.G., et al. Cross talk between the response regulators PhoB and TctD allows for the integration of diverse environmental signals in Pseudomonas aeruginosa. Nucleic Acids Res. 2015;43:6413-6425.
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87.
Dean C.R., Neshat S., Poole K. PfeR, an enterobactin-responsive activator of ferric enterobactin receptor gene expression in Pseudomonas aeruginosa. J. Bacteriol. 1996;178:5361-5369.
Not in our library10.1128/jb.178.18.5361-5369.1996
88.
Ritchings B.W., Almira E.C., Lory S., Ramphal R. Cloning and phenotypic characterization of fleS and fleR, new response regulators of Pseudomonas aeruginosa which regulate motility and adhesion to mucin. Infect. Immun. 1995;63:4868-4876.
Not in our library10.1128/iai.63.12.4868-4876.1995
89.
Yeung A.T., Bains M., Hancock R.E. The sensor kinase CbrA is a global regulator that modulates metabolism, virulence, and antibiotic resistance in Pseudomonas aeruginosa. J. Bacteriol. 2011;193:918-931.
Not in our library10.1128/jb.00911-10
90.
Lukat G.S., Stock J.B. Response regulation in bacterial chemotaxis. J. Cell Biochem. 1993;51:41-46.
Not in our library10.1002/jcb.240510109
91.
Casino P., Rubio V., Marina A. Structural insight into partner specificity and phosphoryl transfer in two-component signal transduction. Cell. 2009;139:325-336.
Not in our library10.1016/j.cell.2009.08.032
92.
Kim D., Forst S. Genomic analysis of the histidine kinase family in bacteria and archaea. Microbiology. 2001;147:1197-1212.
Not in our library10.1099/00221287-147-5-1197
93.
Dereeper A., Guignon V., Blanc G., Audic S., Buffet S., Chevenet F., Dufayard J.F., Guindon S., Lefort V., Lescot M., Claverie J.M., et al. Phylogeny.fr: Robust phylogenetic analysis for the non-specialist. Nucleic Acids Res. 2008;36:W465-W469.
Not in our library10.1093/nar/gkn180
94.
BLAST-EXPLORER helps you building datasets for phylogenetic analysis · 2010
No notice
95.
Dago A.E., Schug A., Procaccini A., Hoch J.A., Weigt M., Szurmant H. Structural basis of histidine kinase autophosphorylation deduced by integrating genomics, molecular dynamics, and mutagenesis. Proc. Natl. Acad. Sci. USA. 2012;109:E1733-E1742.
Not in our library10.1073/pnas.1201301109
96.
Bhagirath A.Y., Pydi S.P., Li Y., Lin C., Kong W., Chelikani P., Duan K. Characterization of the direct Interaction between hybrid sensor kinases PA1611 and RetS that controls biofilm formation and the type III secretion system in Pseudomonas aeruginosa. ACS Infect. Dis. 2017;3:162-175.
Not in our library10.1021/acsinfecdis.6b00153
97.
Ulrich L., Koonin E., Zhulin I. One-component systems dominate signal transduction in prokaryotes. Curr. Trends Microbiol. 2005;13:52-56.
Not in our library10.1016/j.tim.2004.12.006
98.
Koretke K., Lupas A., Warren P., Rosenberg M., Brown J. Evolution of two-component signal transduction. Mol. Biol. Evol. 2000;17:1956-1970.
Not in our library10.1093/oxfordjournals.molbev.a026297
99.
Goodman A.L., Kulasekara B., Rietsch A., Boyd D., Smith R.S., Lory S. A signaling network reciprocally regulates genes associated with acute infection and chronic persistence in Pseudomonas aeruginosa. Dev. Cell. 2004;7:745-754.
Not in our library10.1016/j.devcel.2004.08.020
100.
Goodman A.L., Merighi M., Hyodo M., Ventre I., Filloux A., Lory S. Direct interaction between sensor kinase proteins mediates acute and chronic disease phenotypes in a bacterial pathogen. Genes Dev. 2009;23:249-259.
Not in our library10.1101/gad.1739009
101.
Chambonnier G., Roux L., Redelberger D., Fadel F., Filloux A., Sivaneson M., de Bentzmann S., Bordi C. The hybrid histidine kinase LadS forms a multicomponent signal transduction system with the GacS/GacA two-component system in Pseudomonas aeruginosa. PLoS Genet. 2016;12:e1006032.
Not in our library10.1371/journal.pgen.1006032
102.
Mitrophanov A., Groisman E. Signal integration in bacterial two-component regulatory systems. Genes Dev. 2008;22:2601-2611.
Not in our library10.1101/gad.1700308
103.
Ramos P.I., Custodio M.G., Quispe Saji G.D., Cardoso T., da Silva G.L., Braun G., Martins W.M., Girardello R., de Vasconcelos A.T., Fernandez E., et al. The polymyxin B-induced transcriptomic response of a clinical, multidrug-resistant Klebsiella pneumoniae involves multiple regulatory elements and intracellular targets. BMC Genom. 2016;17:737.
Not in our library10.1186/s12864-016-3070-y
104.
Babouee Flury B., Dona V., Buetti N., Furrer H., Endimiani A. First two cases of severe multifocal infections caused by Klebsiella pneumoniae in Switzerland: Characterization of an atypical non-K1/K2-serotype strain causing liver abscess and endocarditis. J. Glob. Antimicrob. Resist. 2017;10:165-170.
Not in our library10.1016/j.jgar.2017.04.006
105.
The Capsule Regulatory Network of Klebsiella pneumoniae Defined by density-TraDISort · 2018
No notice
106.
Merighi M., Carroll-Portillo A., Septer A.N., Bhatiya A., Gunn J.S. Role of Salmonella enterica serovar typhimurium two-component system PreA/PreB in modulating PmrA-regulated gene transcription. J. Bacteriol. 2006;188:141-149.
Not in our library10.1128/jb.188.1.141-149.2006
107.
Mourey L., Da Re S., Pedelacq J., Tolstykh T., Faurie C., Guillet V., Stock J., Samama J. Crystal structure of the CheA histidine phosphotransfer domain that mediates response regulator phosphorylation in bacterial chemotaxis. J. Biol. Chem. 2001;276:31074-31082.
Not in our library10.1074/jbc.m101943200
108.
Schaller G.E., Shiu S.H., Armitage J.P. Two-component systems and their co-option for eukaryotic signal transduction. Curr. Biol. 2011;21:R320-R330.
Not in our library10.1016/j.cub.2011.02.045
109.
Pena-Sandoval G.R., Kwon O., Georgellis D. Requirement of the receiver and phosphotransfer domains of ArcB for efficient dephosphorylation of phosphorylated ArcA in vivo. J. Bacteriol. 2005;187:3267-3272.
Not in our library10.1128/jb.187.9.3267-3272.2005
110.
Dingemans J., Al-Feghali R.E., Lau G.W., Sauer K. Controlling chronic Pseudomonas aeruginosa infections by strategically interfering with the sensory function of SagS. Mol. Microbiol. 2019.
Not in our library10.1111/mmi.14215
111.
The Yin and Yang of SagS: Distinct Residues in the HmsP Domain of SagS Independently Regulate Biofilm Formation and Biofilm Drug Tolerance · 2018
Not checked
112.
Pamp S.J., Gjermansen M., Johansen H.K., Tolker-Nielsen T. Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes. Mol. Microbiol. 2008;68:223-240.
Not in our library10.1111/j.1365-2958.2008.06152.x
113.
Gupta K., Liao J., Petrova O.E., Cherny K.E., Sauer K. Elevated levels of the second messenger c-di-GMP contribute to antimicrobial resistance of Pseudomonas aeruginosa. Mol. Microbiol. 2014;92:488-506.
Not in our library10.1111/mmi.12587
114.
Gardner S.G., Miller J.B., Dean T., Robinson T., Erickson M., Ridge P.G., McCleary W.R. Genetic analysis, structural modeling, and direct coupling analysis suggest a mechanism for phosphate signaling in Escherichia coli. BMC Genet. 2015;16:S2.
Not in our library10.1186/1471-2156-16-s2-s2
115.
Mitchell S.L., Ismail A.M., Kenrick S.A., Camilli A. The VieB auxiliary protein negatively regulates the VieSA signal transduction system in Vibrio cholerae. BMC Microbiol. 2015;15:59.
Not in our library10.1186/s12866-015-0387-7
116.
Airola M.V., Watts K.J., Bilwes A.M., Crane B.R. Structure of concatenated HAMP domains provides a mechanism for signal transduction. Structure. 2010;18:436-448.
Not in our library10.1016/j.str.2010.01.013
117.
Hsing W., Silhavy T.J. Function of conserved histidine-243 in phosphatase activity of EnvZ, the sensor for porin osmoregulation in Escherichia coli. J. Bacteriol. 1997;179:3729-3735.
Not in our library10.1128/jb.179.11.3729-3735.1997
118.
Matamouros S., Hager K.R., Miller S.I. HAMP domain rotation and tilting movements associated with signal transduction in the PhoQ sensor kinase. mBio. 2015;6:e00616-15.
Not in our library10.1128/mbio.00616-15
119.
Meena N., Kaur H., Mondal A.K. Interactions among HAMP domain repeats act as an osmosensing molecular switch in group III hybrid histidine kinases from fungi. J. Biol. Chem. 2010;285:12121-12132.
Not in our library10.1074/jbc.m109.075721
120.
Muzamal U., Gomez D., Kapadia F., Golemi-Kotra D. Diversity of two-component systems: Insights into the signal transduction mechanism by the Staphylococcus aureus two-component system GraSR. F1000Res. 2014;3:252.
Not in our library10.12688/f1000research.5512.1
121.
Hellingwerf K.J., Postma P.W., Tommassen J., Westerhoff H.V. Signal transduction in bacteria: Phospho-neural network(s) in Escherichia coli? FEMS Microbiol. Rev. 1995;16:309-321.
Not in our library10.1111/j.1574-6976.1995.tb00178.x
122.
Gronlund A. Networking genetic regulation and neural computation: Directed network topology and its effect on the dynamics. Phys. Rev. E Stat. Nonlin Soft Matter Phys. 2004;70:061908.
Not in our library10.1103/physreve.70.061908
123.
Huynh T.N., Chen L.L., Stewart V. Sensor-response regulator interactions in a cross-regulated signal transduction network. Microbiology. 2015;161:1504-1515.
Not in our library10.1099/mic.0.000092
124.
Firon A., Tazi A., Da Cunha V., Brinster S., Sauvage E., Dramsi S., Golenbock D.T., Glaser P., Poyart C., Trieu-Cuot P. The Abi-domain protein Abx1 interacts with the CovS histidine kinase to control virulence gene expression in group B Streptococcus. PLoS Pathog. 2013;9:e1003179.
Not in our library10.1371/journal.ppat.1003179
125.
Gendrin C., Lembo A., Whidbey C., Burnside K., Berry J., Ngo L., Banerjee A., Xue L., Arrington J., Doran K.S., Tao W.A., et al. The sensor histidine kinase RgfC affects group B streptococcal virulence factor expression independent of its response regulator RgfA. Infect. Immun. 2015;83:1078-1088.
Not in our library10.1128/iai.02738-14
126.
He Y.W., Wang C., Zhou L., Song H., Dow J.M., Zhang L.H. Dual signaling functions of the hybrid sensor kinase RpfC of Xanthomonas campestris involve either phosphorelay or receiver domain-protein interaction. J. Biol. Chem. 2006;281:33414-33421.
Not in our library10.1074/jbc.m606571200
127.
Reisinger S.J., Huntwork S., Viollier P.H., Ryan K.R. DivL performs critical cell cycle functions in Caulobacter crescentus independent of kinase activity. J. Bacteriol. 2007;189:8308-8320.
Not in our library10.1128/jb.00868-07
128.
Gao R., Stock A.M. Biological insights from structures of two-component proteins. Annu. Rev. Microbiol. 2009;63:133-154.
Not in our library10.1146/annurev.micro.091208.073214
129.
Kong W., Chen L., Zhao J., Shen T., Surette M., Shen L., Duan K. Hybrid sensor kinase PA1611 in Pseudomonas aeruginosa regulates transitions between acute and chronic infection through direct interaction with RetS. Mol. Microbiol. 2013;88:784-797.
Not in our library10.1111/mmi.12223
130.
Chen L., Duan K. A PhoPQ-regulated ABC transporter system exports Tetracycline in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2016;60:3016-3024.
Not in our library10.1128/aac.02986-15
131.
Wilton M., Charron-Mazenod L., Moore R., Lewenza S. Extracellular DNA acidifies biofilms and Induces aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2016;60:544-553.
Not in our library10.1128/aac.01650-15
132.
McPhee J.B., Bains M., Winsor G., Lewenza S., Kwasnicka A., Brazas M.D., Brinkman F.S., Hancock R.E. Contribution of the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems to Mg2+-induced gene regulation in Pseudomonas aeruginosa. J. Bacteriol. 2006;188:3995-4006.
Not in our library10.1128/jb.00053-06
133.
The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is shaped by strong epistatic interactions · 2016
No notice
134.
Moskowitz S.M., Ernst R.K., Miller S.I. PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A. J. Bacteriol. 2004;186:575-579.
Not in our library10.1128/jb.186.2.575-579.2004
135.
Barbosa C., Trebosc V., Kemmer C., Rosenstiel P., Beardmore R., Schulenburg H., Jansen G. Alternative evolutionary paths to bacterial antibiotic resistance cause distinct collateral effects. Mol. Biol. Evol. 2017;34:2229-2244.
Not in our library10.1093/molbev/msx158
136.
Tian Z.X., Yi X.X., Cho A., O’Gara F., Wang Y.P. CpxR Activates MexAB-OprM Efflux Pump Expression and Enhances Antibiotic Resistance in Both Laboratory and Clinical nalB-Type Isolates of Pseudomonas aeruginosa. PLoS Pathog. 2016;12:e1005932.
Not in our library10.1371/journal.ppat.1005932
137.
Fernandez L., Gooderham W.J., Bains M., McPhee J.B., Wiegand I., Hancock R.E. Adaptive resistance to the “last hope” antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by the novel two-component regulatory system ParR-ParS. Antimicrob. Agents Chemother. 2010;54:3372-3382.
Not in our library10.1128/aac.00242-10
138.
Muller C., Plesiat P., Jeannot K. A two-component regulatory system interconnects resistance to polymyxins, aminoglycosides, fluoroquinolones, and beta-lactams in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2011;55:1211-1221.
Not in our library10.1128/aac.01252-10
139.
The Formation of Biofilms by Pseudomonas aeruginosa : A Review of the Natural and Synthetic Compounds Interfering with Control Mechanisms · 2015
No notice
140.
Expression of Pseudomonas aeruginosa CupD fimbrial genes is antagonistically controlled by RcsB and the EAL-containing PvrR response regulators. · 2009
Not checked
141.
Mikkelsen H., Hui K., Barraud N., Filloux A. The pathogenicity island encoded PvrSR/RcsCB regulatory network controls biofilm formation and dispersal in Pseudomonas aeruginosa PA14. Mol. Microbiol. 2013;89:450-463.
Not in our library10.1111/mmi.12287
142.
Drenkard E., Ausubel F.M. Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature. 2002;416:740-743.
Not in our library10.1038/416740a
143.
Sivaneson M., Mikkelsen H., Ventre I., Bordi C., Filloux A. Two-component regulatory systems in Pseudomonas aeruginosa: An intricate network mediating fimbrial and efflux pump gene expression. Mol. Microbiol. 2011;79:1353-1366.
Not in our library10.1111/j.1365-2958.2010.07527.x
144.
Lau C.H., Fraud S., Jones M., Peterson S.N., Poole K. Mutational activation of the AmgRS two-component system in aminoglycoside-resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2013;57:2243-2251.
Not in our library10.1128/aac.00170-13
145.
Lau C.H., Krahn T., Gilmour C., Mullen E., Poole K. AmgRS-mediated envelope stress-inducible expression of the mexXY multidrug efflux operon of Pseudomonas aeruginosa. Microbiologyopen. 2015;4:121-135.
Not in our library10.1002/mbo3.226
146.
Fruci M., Poole K. Aminoglycoside-inducible expression of the mexAB-oprM multidrug efflux operon in Pseudomonas aeruginosa: Involvement of the envelope stress-responsive AmgRS two-component system. PLoS ONE. 2018;13:e0205036.
Not in our library10.1371/journal.pone.0205036
147.
A Novel Signaling Network Essential for Regulating Pseudomonas aeruginosa Biofilm Development · 2009
No notice
148.
Hsu J.L., Chen H.C., Peng H.L., Chang H.Y. Characterization of the histidine-containing phosphotransfer protein B-mediated multistep phosphorelay system in Pseudomonas aeruginosa PAO1. J. Biol. Chem. 2008;283:9933-9944.
Not in our library10.1074/jbc.m708836200
149.
Bhuwan M., Lee H.J., Peng H.L., Chang H.Y. Histidine-containing phosphotransfer protein-B (HptB) regulates swarming motility through partner-switching system in Pseudomonas aeruginosa PAO1 strain. J. Biol. Chem. 2012;287:1903-1914.
Not in our library10.1074/jbc.m111.256586
150.
Kulasekara H.D., Ventre I., Kulasekara B.R., Lazdunski A., Filloux A., Lory S. A novel two-component system controls the expression of Pseudomonas aeruginosa fimbrial cup genes. Mol. Microbiol. 2005;55:368-380.
Not in our library10.1111/j.1365-2958.2004.04402.x
151.
Beaudoin T., Zhang L., Hinz A.J., Parr C.J., Mah T.F. The biofilm-specific antibiotic resistance gene ndvB is important for expression of ethanol oxidation genes in Pseudomonas aeruginosa biofilms. J. Bacteriol. 2012;194:3128-3136.
Not in our library10.1128/jb.06178-11
152.
Blus-Kadosh I., Zilka A., Yerushalmi G., Banin E. The effect of pstS and phoB on quorum sensing and swarming motility in Pseudomonas aeruginosa. PLoS ONE. 2013;8:e74444.
Not in our library10.1371/journal.pone.0074444
153.
A Hierarchical Cascade of Second Messengers Regulates <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Surface Behaviors · 2015
Not checked
154.
Fulcher N.B., Holliday P.M., Klem E., Cann M.J., Wolfgang M.C. The Pseudomonas aeruginosa Chp chemosensory system regulates intracellular cAMP levels by modulating adenylate cyclase activity. Mol. Microbiol. 2010;76:889-904.
Not in our library10.1111/j.1365-2958.2010.07135.x
155.
Intile P.J., Diaz M.R., Urbanowski M.L., Wolfgang M.C., Yahr T.L. The AlgZR two-component system recalibrates the RsmAYZ posttranscriptional regulatory system to inhibit expression of the Pseudomonas aeruginosa type III secretion system. J. Bacteriol. 2014;196:357-366.
Not in our library10.1128/jb.01199-13
156.
Zamorano L., Moya B., Juan C., Mulet X., Blazquez J., Oliver A. The Pseudomonas aeruginosa CreBC two-component system plays a major role in the response to beta-lactams, fitness, biofilm growth, and global regulation. Antimicrob. Agents Chemother. 2014;58:5084-5095.
Not in our library10.1128/aac.02556-14
157.
Vasil M.L., Ochsner U.A. The response of Pseudomonas aeruginosa to iron: Genetics, biochemistry and virulence. Mol. Microbiol. 1999;34:399-413.
Not in our library10.1046/j.1365-2958.1999.01586.x
158.
Dasgupta N., Wolfgang M.C., Goodman A.L., Arora S.K., Jyot J., Lory S., Ramphal R. A four-tiered transcriptional regulatory circuit controls flagellar biogenesis in Pseudomonas aeruginosa. Mol. Microbiol. 2003;50:809-824.
Not in our library10.1046/j.1365-2958.2003.03740.x
159.
Ryan R.P., Fouhy Y., Garcia B.F., Watt S.A., Niehaus K., Yang L., Tolker-Nielsen T., Dow J.M. Interspecies signalling via the Stenotrophomonas maltophilia diffusible signal factor influences biofilm formation and polymyxin tolerance in Pseudomonas aeruginosa. Mol. Microbiol. 2008;68:75-86.
Not in our library10.1111/j.1365-2958.2008.06132.x
160.
Perron K., Caille O., Rossier C., Van Delden C., Dumas J.L., Kohler T. CzcR-CzcS, a two-component system involved in heavy metal and carbapenem resistance in Pseudomonas aeruginosa. J. Biol. Chem. 2004;279:8761-8768.
Not in our library10.1074/jbc.m312080200
161.
Caille O., Rossier C., Perron K. A copper-activated two-component system interacts with zinc and imipenem resistance in Pseudomonas aeruginosa. J. Bacteriol. 2007;189:4561-4568.
Not in our library10.1128/jb.00095-07
162.
Laskowski M.A., Osborn E., Kazmierczak B.I. A novel sensor kinase-response regulator hybrid regulates type III secretion and is required for virulence in Pseudomonas aeruginosa. Mol. Microbiol. 2004;54:1090-1103.
Not in our library10.1111/j.1365-2958.2004.04331.x
163.
Kreamer N.N., Costa F., Newman D.K. The ferrous iron-responsive BqsRS two-component system activates genes that promote cationic stress tolerance. mBio. 2015;6:e02549.
Not in our library10.1128/mbio.02549-14
164.
Sage A.E., Proctor W.D., Phibbs P.V. A two-component response regulator, gltR, is required for glucose transport activity in Pseudomonas aeruginosa PAO1. J. Bacteriol. 1996;178:6064-6066.
Not in our library10.1128/jb.178.20.6064-6066.1996
165.
Wolfgang M.C., Lee V.T., Gilmore M.E., Lory S. Coordinate regulation of bacterial virulence genes by a novel adenylate cyclase-dependent signaling pathway. Dev. Cell. 2003;4:253-263.
Not in our library10.1016/s1534-5807(03)00019-4
166.
Huangyutitham V., Guvener Z.T., Harwood C.S. Subcellular clustering of the phosphorylated WspR response regulator protein stimulates its diguanylate cyclase activity. mBio. 2013;4:e00242-13.
Not in our library10.1128/mbio.00242-13
167.
Pseudomonas aeruginosa uses a cyclic‐di‐GMP‐regulated adhesin to reinforce the biofilm extracellular matrix · 2010
No notice
168.
Hickman J.W., Tifrea D.F., Harwood C.S. A chemosensory system that regulates biofilm formation through modulation of cyclic diguanylate levels. Proc. Natl. Acad. Sci. USA. 2005;102:14422-14427.
Not in our library10.1073/pnas.0507170102
169.
Wang Y., Ha U., Zeng L., Jin S. Regulation of membrane permeability by a two-component regulatory system in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2003;47:95-101.
Not in our library10.1128/aac.47.1.95-101.2003
170.
Giraud C., Bernard C.S., Calderon V., Yang L., Filloux A., Molin S., Fichant G., Bordi C., de Bentzmann S. The PprA-PprB two-component system activates CupE, the first non-archetypal Pseudomonas aeruginosa chaperone-usher pathway system assembling fimbriae. Environ. Microbiol. 2011;13:666-683.
Not in our library10.1111/j.1462-2920.2010.02372.x
171.
De Bentzmann S., Giraud C., Bernard C.S., Calderon V., Ewald F., Plesiat P., Nguyen C., Grunwald D., Attree I., Jeannot K., et al. Unique biofilm signature, drug susceptibility and decreased virulence in Drosophila through the Pseudomonas aeruginosa two-component system PprAB. PLoS Pathog. 2012;8:e1003052.
Not in our library10.1371/annotation/5c169544-7d19-40db-9a58-28b2fdf2c82c
172.
Hurley B.P., Goodman A.L., Mumy K.L., Murphy P., Lory S., McCormick B.A. The two-component sensor response regulator RoxS/RoxR plays a role in Pseudomonas aeruginosa interactions with airway epithelial cells. Microbes Infect. 2010;12:190-198.
Not in our library10.1016/j.micinf.2009.11.009
173.
Kilmury S.L.N., Burrows L.L. The Pseudomonas aeruginosa PilSR two-component system regulates both twitching and swimming motilities. mBio. 2018;9:e01310-18.
Not in our library10.1128/mbio.01310-18
174.
Beckmann C., Brittnacher M., Ernst R., Mayer-Hamblett N., Miller S.I., Burns J.L. Use of phage display to identify potential Pseudomonas aeruginosa gene products relevant to early cystic fibrosis airway infections. Infect. Immun. 2005;73:444-452.
Not in our library10.1128/iai.73.1.444-452.2005
175.
Yang Z., Lu C.D. Functional genomics enables identification of genes of the arginine transaminase pathway in Pseudomonas aeruginosa. J. Bacteriol. 2007;189:3945-3953.
Not in our library10.1128/jb.00261-07
176.
Li W., Lu C.D. Regulation of carbon and nitrogen utilization by CbrAB and NtrBC two-component systems in Pseudomonas aeruginosa. J. Bacteriol. 2007;189:5413-5420.
Not in our library10.1128/jb.00432-07
177.
Valentini M., Storelli N., Lapouge K. Identification of C(4)-dicarboxylate transport systems in Pseudomonas aeruginosa PAO1. J. Bacteriol. 2011;193:4307-4316.
Not in our library10.1128/jb.05074-11
178.
Chand N.S., Clatworthy A.E., Hung D.T. The two-component sensor KinB acts as a phosphatase to regulate Pseudomonas aeruginosa Virulence. J. Bacteriol. 2012;194:6537-6547.
Not in our library10.1128/jb.01168-12
179.
Pseudomonas aeruginosa MifS-MifR Two-Component System Is Specific for α-Ketoglutarate Utilization. · 2015
Not checked
180.
Srinivasan V.B., Vaidyanathan V., Mondal A., Rajamohan G. Role of the two component signal transduction system CpxAR in conferring cefepime and chloramphenicol resistance in Klebsiella pneumoniae NTUH-K2044. PLoS ONE. 2012;7:e33777.
Not in our library10.1371/journal.pone.0033777
181.
Raivio T.L. Envelope stress responses and Gram-negative bacterial pathogenesis. Mol. Microbiol. 2005;56:1119-1128.
Not in our library10.1111/j.1365-2958.2005.04625.x
182.
Cannatelli A., D’Andrea M.M., Giani T., Di Pilato V., Arena F., Ambretti S., Gaibani P., Rossolini G.M. In vivo emergence of colistin resistance in Klebsiella pneumoniae producing KPC-type carbapenemases mediated by insertional inactivation of the PhoQ/PhoP mgrB regulator. Antimicrob. Agents Chemother. 2013;57:5521-5526.
Not in our library10.1128/aac.01480-13
183.
Jayol A., Nordmann P., Brink A., Poirel L. Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. Antimicrob. Agents Chemother. 2015;59:2780-2784.
Not in our library10.1128/aac.05055-14
184.
Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide · 2009
No notice
185.
Sperandio V., Torres A.G., Kaper J.B. Quorum sensing Escherichia coli regulators B and C (QseBC): A novel two-component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli. Mol. Microbiol. 2002;43:809-821.
Not in our library10.1046/j.1365-2958.2002.02803.x
186.
Lai Y.C., Lin G.T., Yang S.L., Chang H.Y., Peng H.L. Identification and characterization of KvgAS, a two-component system in Klebsiella pneumoniae CG43. Fems Microbiol. Lett. 2003;218:121-126.
Not in our library10.1111/j.1574-6968.2003.tb11507.x
187.
Lin C.T., Huang T.Y., Liang W.C., Peng H.L. Homologous response regulators KvgA, KvhA and KvhR regulate the synthesis of capsular polysaccharide in Klebsiella pneumoniae CG43 in a coordinated manner. J. Biochem. 2006;140:429-438.
Not in our library10.1093/jb/mvj168
188.
Lin C.T., Peng H.L. Regulation of the homologous two-component systems KvgAS and KvhAS in Klebsiella pneumoniae CG43. J. Biochem. 2006;140:639-648.
Not in our library10.1093/jb/mvj196
189.
Cannatelli A., Di Pilato V., Giani T., Arena F., Ambretti S., Gaibani P., D’Andrea M.M., Rossolini G.M. In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment. Antimicrob. Agents Chemother. 2014;58:4399-4403.
Not in our library10.1128/aac.02555-14
190.
Su K., Zhou X., Luo M., Xu X., Liu P., Li X., Xue J., Chen S., Xu W., Li Y., Qiu J. Genome-wide identification of genes regulated by RcsA, RcsB, and RcsAB phosphorelay regulators in Klebsiella pneumoniae NTUH-K2044. Microb. Pathog. 2018;123:36-41.
Not in our library10.1016/j.micpath.2018.06.036
191.
Nixon B.T., Ronson C.W., Ausubel F.M. Two-component regulatory systems responsive to environmental stimuli share strongly conserved domains with the nitrogen assimilation regulatory genes ntrB and ntrC. Proc. Natl. Acad. Sci. USA. 1986;83:7850-7854.
Not in our library10.1073/pnas.83.20.7850
192.
Hsing W.H., Russo F.D., Bernd K.K., Silhavy T.J. Mutations that alter the kinase and phosphatase activities of the two-component sensor EnvZ. J. Bacteriol. 1998;180:4538-4546.
Not in our library10.1128/jb.180.17.4538-4546.1998
193.
Lin T.H., Chen Y., Kuo J.T., Lai Y.C., Wu C.C., Huang C.F., Lin C.T. Phosphorylated OmpR Is required for type 3 fimbriae expression in Klebsiella pneumoniae under hypertonic conditions. Front. Microbiol. 2018;9:2405.
Not in our library10.3389/fmicb.2018.02405
194.
Zahid N., Zulfiqiar S., Shakoori A.R. Functional analysis of cus operon promoter of Klebsiella pneumoniae using E. coli lacZ assay. Gene. 2012;495:81-88.
Not in our library10.1016/j.gene.2011.12.040
195.
Chaturvedi K.S., Henderson J.P. Pathogenic adaptations to host-derived antibacterial copper. Front. Cell. Infect. Microbiol. 2014;4:3.
Not in our library10.3389/fcimb.2014.00003
196.
Hanczvikkel A., Fuzi M., Ungvari E., Toth A. Transmissible silver resistance readily evolves in high-risk clone isolates of Klebsiella pneumoniae. Acta Microbiol. Immunol. Hung. 2018;65:387-403.
Not in our library10.1556/030.65.2018.031
197.
Goulian M. Two-component signaling circuit structure and properties. Curr. Opin. Microbiol. 2010;13:184-189.
Not in our library10.1016/j.mib.2010.01.009
198.
Pfluger-Grau K., Gorke B. Regulatory roles of the bacterial nitrogen-related phosphotransferase system. Curr. Trends Microbiol. 2010;18:205-214.
Not in our library10.1016/j.tim.2010.02.003
199.
Zhou L., Lei X.H., Bochner B.R., Wanner B.L. Phenotype microarray analysis of Escherichia coli K-12 mutants with deletions of all two-component systems. J. Bacteriol. 2003;185:4956-4972.
Not in our library10.1128/jb.185.16.4956-4972.2003
200.
Nagakubo S., Nishino K., Hirata T., Yamaguchi A. The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC. J. Bacteriol. 2002;184:4161-4167.
Not in our library10.1128/jb.184.15.4161-4167.2002
201.
Perrenoud A., Sauer U. Impact of global transcriptional regulation by ArcA, ArcB, Cra, Crp, Cya, Fnr, and Mlc on glucose catabolism in Escherichia coli. J. Bacteriol. 2005;187:3171-3179.
Not in our library10.1128/jb.187.9.3171-3179.2005
202.
Lin J.T., Goldman B.S., Stewart V. Structures of genes nasA and nasB, encoding assimilatory nitrate and nitrite reductases in Klebsiella Pneumoniae M5al. J. Bacteriol. 1993;175:2370-2378.
Not in our library10.1128/jb.175.8.2370-2378.1993
203.
Moreno-Vivian C., Cabello P., Martinez-Luque M., Blasco R., Castillo F. Prokaryotic nitrate reduction: Molecular properties and functional distinction among bacterial nitrate reductases. J. Bacteriol. 1999;181:6573-6584.
Not in our library10.1128/jb.181.21.6573-6584.1999
204.
Verhamme D.T., Postma P.W., Crielaard W., Hellingwerf K.J. Cooperativity in signal transfer through the Uhp system of Escherichia coli. J. Bacteriol. 2002;184:4205-4210.
Not in our library10.1128/jb.184.15.4205-4210.2002
205.
Molecular Mechanisms and Clinical Impact of Acquired and Intrinsic Fosfomycin Resistance · 2013
No notice
206.
Luo S.C., Lou Y.C., Rajasekaran M., Chang Y.W., Hsiao C.D., Chen C. Structural basis of a physical blockage mechanism for the interaction of response regulator PmrA with connector protein PmrD from Klebsiella pneumoniae. J. Biol. Chem. 2013;288:25551-25561.
Not in our library10.1074/jbc.m113.481978
207.
Nishino K., Yamaguchi A. EvgA of the two-component signal transduction system modulates production of the YhiUV multidrug transporter in Escherichia coli. J. Bacteriol. 2002;184:2319-2323.
Not in our library10.1128/jb.184.8.2319-2323.2002
208.
Chen Y.M., Backman K., Magasanik B. Characterization of a Gene, glnl, the Product of Which Is Involved in the Regulation of Nitrogen-Utilization in Escherichia coli. J. Bacteriol. 1982;150:214-220.
Not in our library10.1128/jb.150.1.214-220.1982
209.
Claveriemartin F., Magasanik B. Positive and negative effects of DNA bending on activation of transcription from a distant site. J. Mol. Biol. 1992;227:996-1008.
Not in our library10.1016/0022-2836(92)90516-m
210.
Sallai L., Tucker P.A. Crystal structure of the central and C-terminal domain of the sigma(54)-activator ZraR. J. Struct. Biol. 2005;151:160-170.
Not in our library10.1016/j.jsb.2005.05.006
211.
Scheu P.D., Witan J., Rauschmeier M., Graf S., Liao Y.F., Ebert-Jung A., Basche T., Erker W., Unden G. CitA/CitB two-component system regulating citrate fermentation in Escherichia coli and its relation to the DcuS/DcuR system in vivo. J. Bacteriol. 2012;194:636-645.
Not in our library10.1128/jb.06345-11
212.
Meyer M., Dimroth P., Bott M. Catabolite repression of the citrate fermentation genes in Klebsiella pneumoniae: Evidence for involvement of the cyclic AMP receptor protein. J. Bacteriol. 2001;183:5248-5256.
Not in our library10.1128/jb.183.18.5248-5256.2001
213.
Cheng Y.H., Lin T.L., Lin Y.T., Wang J.T. Amino acid substitutions of CrrB responsible for resistance to colistin through CrrC in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 2016;60:3709-3716.
Not in our library10.1128/aac.00009-16
214.
Lean S.S., Yeo C.C., Suhaili Z., Thong K.L. Comparative genomics of two ST 195 carbapenem-resistant Acinetobacter baumannii with different susceptibility to polymyxin revealed underlying resistance mechanism. Front. Microbiol. 2015;6:1445.
Not in our library10.3389/fmicb.2015.01445
215.
Jaidane N., Naas T., Mansour W., Radhia B.B., Jerbi S., Boujaafar N., Bouallegue O., Bonnin R.A. Genomic analysis of in vivo acquired resistance to colistin and rifampicin in Acinetobacter baumannii. Int. J. Antimicrob. Agents. 2018;51:266-269.
Not in our library10.1016/j.ijantimicag.2017.10.016
216.
The Acinetobacter baumannii Two-Component System AdeRS Regulates Genes Required for Multidrug Efflux, Biofilm Formation, and Virulence in a Strain-Specific Manner · 2016
Corrected
217.
Lin M.F., Lin Y.Y., Yeh H.W., Lan C.Y. Role of the BaeSR two-component system in the regulation of Acinetobacter baumannii adeAB genes and its correlation with tigecycline susceptibility. BMC Microbiol. 2014;14:119.
Not in our library10.1186/1471-2180-14-119
218.
Lin M.F., Lin Y.Y., Lan C.Y. The role of the two-component system BaeSR in disposing chemicals through regulating transporter systems in Acinetobacter baumannii. PLoS ONE. 2015;10:e0132843.
Not in our library10.1371/journal.pone.0132843
219.
Tomaras A.P., Flagler M.J., Dorsey C.W., Gaddy J.A., Actis L.A. Characterization of a two-component regulatory system from Acinetobacter baumannii that controls biofilm formation and cellular morphology. Microbiology. 2008;154:3398-3409.
Not in our library10.1099/mic.0.2008/019471-0
220.
Liou M.L., Soo P.C., Ling S.R., Kuo H.Y., Tang C.Y., Chang K.C. The sensor kinase BfmS mediates virulence in Acinetobacter baumannii. J. Microbiol. Immunol. Infect. 2014;47:275-281.
Not in our library10.1016/j.jmii.2012.12.004
221.
Russo T.A., Manohar A., Beanan J.M., Olson R., MacDonald U., Graham J., Umland T.C. The response regulator BfmR is a potential drug target for Acinetobacter baumannii. mSphere. 2016;1:e00082-16.
Not in our library10.1128/msphere.00082-16
222.
Cerqueira G.M., Kostoulias X., Khoo C., Aibinu I., Qu Y., Traven A., Peleg A.Y. A global virulence regulator in Acinetobacter baumannii and its control of the phenylacetic acid catabolic pathway. J. Infect. Dis. 2014;210:46-55.
Not in our library10.1093/infdis/jiu024
223.
Bhuiyan M.S., Ellett F., Murray G.L., Kostoulias X., Cerqueira G.M., Schulze K.E., Mahamad Maifiah M.H., Li J., Creek D.J., Lieschke G.J., et al. Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis. Proc. Natl. Acad. Sci. USA. 2016;113:9599-9604.
Not in our library10.1073/pnas.1523116113
224.
Chen R., Lv R., Xiao L., Wang M., Du Z., Tan Y., Cui Y., Yan Y., Luo Y., Yang R., et al. A1S_2811, a CheA/Y-like hybrid two-component regulator from Acinetobacter baumannii ATCC17978, is involved in surface motility and biofilm formation in this bacterium. Microbiologyopen. 2017;6:e00510.
Not in our library10.1002/mbo3.510
225.
Samir R., Hussein S.H., Elhosseiny N.M., Khattab M.S., Shawky A.E., Attia A.S. Adaptation to potassium-limitation is essential for Acinetobacter baumannii pneumonia pathogenesis. J. Infect. Dis. 2016;214:2006-2013.
Not in our library10.1093/infdis/jiw476
226.
Ninfa A.J., Magasanik B. Covalent modification of the glnG product, NRI, by the glnL product, NRII, regulates the transcription of the glnALG operon in Escherichia coli. Proc. Natl. Acad. Sci. USA. 1986;83:5909-5913.
Not in our library10.1073/pnas.83.16.5909
227.
Gavigan J.A., Marshall L.M., Dobson A.D. Regulation of polyphosphate kinase gene expression in Acinetobacter baumannii 252. Microbiology. 1999;145:2931-2937.
Not in our library10.1099/00221287-145-10-2931
228.
Williams C.L., Neu H.M., Gilbreath J.J., Michel S.L., Zurawski D.V., Merrell D.S. Copper resistance of the emerging pathogen Acinetobacter baumannii. Appl. Environ. Microbiol. 2016;82:6174-6188.
Not in our library10.1128/aem.01813-16
229.
Tipton K.A., Rather P.N. An OmpR-EnvZ two-component system ortholog regulates phase variation, osmotic tolerance, motility, and virulence in Acinetobacter baumannii Strain AB5075. J. Bacteriol. 2017;199:e00705-16.
Not in our library10.1128/jb.00705-16
230.
Extracellular DNA Chelates Cations and Induces Antibiotic Resistance in Pseudomonas aeruginosa Biofilms · 2008
No notice
231.
McPhee J.B., Lewenza S., Hancock R.E. Cationic antimicrobial peptides activate a two-component regulatory system, PmrA-PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa. Mol. Microbiol. 2003;50:205-217.
Not in our library10.1046/j.1365-2958.2003.03673.x
232.
Schniederjans M., Koska M., Häussler S. Transcriptional and mutational profiling of an aminoglycoside-resistant Pseudomonas aeruginosa small-colony variant. Antimicrob. Agents Chemother. 2017;61:e01178-17.
Not in our library10.1128/aac.01178-17
233.
Fothergill J.L., Neill D.R., Loman N., Winstanley C., Kadioglu A. Pseudomonas aeruginosa adaptation in the nasopharyngeal reservoir leads to migration and persistence in the lungs. Nat. Commun. 2014;5:4780.
Not in our library10.1038/ncomms5780
234.
Bricio-Moreno L., Sheridan V.H., Goodhead I., Armstrong S., Wong J.K.L., Waters E.M., Sarsby J., Panagiotou S., Dunn J., Chakraborty A., et al. Evolutionary trade-offs associated with loss of PmrB function in host-adapted Pseudomonas aeruginosa. Nat. Commun. 2018;9:2635.
Not in our library10.1038/s41467-018-04996-x
235.
Nowicki E.M., O’Brien J.P., Brodbelt J.S., Trent M.S. Extracellular zinc induces phosphoethanolamine addition to Pseudomonas aeruginosa lipid A via the ColRS two-component system. Mol. Microbiol. 2015;97:166-178.
Not in our library10.1111/mmi.13018
236.
Molecular characterization of the PhoPQ-PmrD-PmrAB mediated pathway regulating polymyxin B resistance in Klebsiella pneumoniae CG43 · 2010
No notice
237.
Carretero-Ledesma M., García-Quintanilla M., Martín-Peña R., Pulido M.R., Pachón J., McConnell M.J. Phenotypic changes associated with Colistin resistance due to Lipopolysaccharide loss in Acinetobacter baumannii. Virulence. 2018;9:930-942.
Not in our library10.1080/21505594.2018.1460187
238.
Kim Y., Bae I.K., Jeong S.H., Yong D., Lee K. In vivo selection of pan-drug resistant Acinetobacter baumannii during antibiotic treatment. Yonsei Med. J. 2015;56:928-934.
Not in our library10.3349/ymj.2015.56.4.928
239.
Lopez-Rojas R., Dominguez-Herrera J., McConnell M.J., Docobo-Perez F., Smani Y., Fernandez-Reyes M., Rivas L., Pachon J. Impaired virulence and in vivo fitness of colistin-resistant Acinetobacter baumannii. J. Infect. Dis. 2011;203:545-548.
Not in our library10.1093/infdis/jiq086
240.
Durante-Mangoni E., Del Franco M., Andini R., Bernardo M., Giannouli M., Zarrilli R. Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii. Diagn Microbiol. Infect. Dis. 2015;82:222-226.
Not in our library10.1016/j.diagmicrobio.2015.03.013
241.
Lopez-Rojas R., Garcia-Quintanilla M., Labrador-Herrera G., Pachon J., McConnell M.J. Impaired growth under iron-limiting conditions associated with the acquisition of colistin resistance in Acinetobacter baumannii. Int. J. Antimicrob. Agents. 2016;47:473-477.
Not in our library10.1016/j.ijantimicag.2016.03.010
242.
Wand M.E., Bock L.J., Bonney L.C., Sutton J.M. Retention of virulence following adaptation to colistin in Acinetobacter baumannii reflects the mechanism of resistance. J. Antimicrob. Chemother. 2015;70:2209-2216.
Not in our library10.1093/jac/dkv097
243.
Da Silva G.J., Domingues S. Interplay between colistin resistance, virulence and fitness in Acinetobacter baumannii. Antibiotics. 2017;6:28.
Not in our library10.3390/antibiotics6040028
244.
Janssen K.H., Diaz M.R., Golden M., Graham J.W., Sanders W., Wolfgang M.C., Yahr T.L. Functional analyses of the RsmY and RsmZ small noncoding regulatory RNAs in Pseudomonas aeruginosa. J. Bacteriol. 2018;200:e00736-17.
Not in our library10.1128/jb.00736-17
245.
Marden J.N., Diaz M.R., Walton W.G., Gode C.J., Betts L., Urbanowski M.L., Redinbo M.R., Yahr T.L., Wolfgang M.C. An unusual CsrA family member operates in series with RsmA to amplify post-transcriptional responses in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA. 2013;110:15055-15060.
Not in our library10.1073/pnas.1307217110
246.
Llanes C., Köhler T., Patry I., Dehecq B., van Delden C., Plésiat P. Role of the MexEF-OprN efflux system in low-level resistance of Pseudomonas aeruginosa to Ciprofloxacin. Antimicrob. Agents Chemother. 2011;55:5676-5684.
Not in our library10.1128/aac.00101-11
247.
MexEF-OprN Efflux Pump Exports the Pseudomonas Quinolone Signal (PQS) Precursor HHQ (4-hydroxy-2-heptylquinoline) · 2011
No notice
248.
Linares J.F., Gustafsson I., Baquero F., Martinez J.L. Antibiotics as intermicrobial signaling agents instead of weapons. Proc. Natl. Acad. Sci. USA. 2006;103:19484-19489.
Not in our library10.1073/pnas.0608949103
249.
Biofilms and Cyclic di-GMP (c-di-GMP) Signaling: Lessons from Pseudomonas aeruginosa and Other Bacteria · 2016
No notice
250.
Ventre I., Goodman A.L., Vallet-Gely I., Vasseur P., Soscia C., Molin S., Bleves S., Lazdunski A., Lory S., Filloux A. Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes. Proc. Natl. Acad. Sci. USA. 2006;103:171-176.
Not in our library10.1073/pnas.0507407103
251.
Moscoso J.A., Mikkelsen H., Heeb S., Williams P., Filloux A. The Pseudomonas aeruginosa sensor RetS switches type III and type VI secretion via c-di-GMP signalling. Environ. Microbiol. 2011;13:3128-3138.
Not in our library10.1111/j.1462-2920.2011.02595.x
252.
Evans T.J. Small colony variants of Pseudomonas aeruginosa in chronic bacterial infection of the lung in cystic fibrosis. Future Microbiol. 2015;10:231-239.
Not in our library10.2217/fmb.14.107
253.
Kentache T., Ben Abdelkrim A., Jouenne T., De E., Hardouin J. Global dynamic proteome study of a pellicle-forming Acinetobacter baumannii strain. Mol. Cell. Proteomics MCP. 2017;16:100-112.
Not in our library10.1074/mcp.m116.061044
254.
Peleg A.Y., Tampakakis E., Fuchs B.B., Eliopoulos G.M., Moellering R.C., Mylonakis E. Prokaryote-eukaryote interactions identified by using Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA. 2008;105:14585-14590.
Not in our library10.1073/pnas.0805048105
255.
Dorsey C.W., Tomaras A.P., Actis L.A. Genetic and phenotypic analysis of Acinetobacter baumannii insertion derivatives generated with a transposome system. Appl. Environ. Microbiol. 2002;68:6353-6360.
Not in our library10.1128/aem.68.12.6353-6360.2002
256.
Suzuki K., Wang X., Weilbacher T., Pernestig A.-K., Melefors O., Georgellis D., Babitzke P., Romeo T. Regulatory circuitry of the CsrA/CsrB and BarA/UvrY systems of Escherichia coli. J. Bacteriol. 2002;184:5130-5140.
Not in our library10.1128/jb.184.18.5130-5140.2002
257.
Tomenius H., Pernestig A.K., Mendez-Catala C.F., Georgellis D., Normark S., Melefors O. Genetic and functional characterization of the Escherichia coli BarA-UvrY two-component system: Point mutations in the HAMP linker of the BarA sensor give a dominant-negative phenotype. J. Bacteriol. 2005;187:7317-7324.
Not in our library10.1128/jb.187.21.7317-7324.2005
258.
Mukhopadhyay S., Audia J.P., Roy R.N., Schellhorn H.E. Transcriptional induction of the conserved alternative sigma factor RpoS in Escherichia coli is dependent on BarA, a probable two-component regulator. Mol. Microbiol. 2000;37:371-381.
Not in our library10.1046/j.1365-2958.2000.01999.x
259.
Mukhopadhyay S., Schellhorn H.E. Identification and characterization of hydrogen peroxide-sensitive mutants of Escherichia coli: Genes that require OxyR for expression. J. Bacteriol. 1997;179:330-338.
Not in our library10.1128/jb.179.2.330-338.1997
260.
Michael B., Smith J.N., Swift S., Heffron F., Ahmer B.M. SdiA of Salmonella enterica is a LuxR homolog that detects mixed microbial communities. J. Bacteriol. 2001;183:5733-5742.
Not in our library10.1128/jb.183.19.5733-5742.2001
261.
Fernando D., Kumar A. Growth phase-dependent expression of RND efflux pump- and outer membrane porin-encoding genes in Acinetobacter baumannii ATCC 19606. J. Antimicrob. Chemother. 2012;67:569-572.
Not in our library10.1093/jac/dkr519
262.
Multidrug Efflux Pumps in Staphylococcus aureus: an Update · 2013
No notice
263.
Ruzin A., Keeney D., Bradford P.A. AdeABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus-Acinetobacter baumannii complex. J. Antimicrob. Chemother. 2007;59:1001-1004.
Not in our library10.1093/jac/dkm058
264.
Vila J., Marti S., Sanchez-Cespedes J. Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii. J. Antimicrob. Chemother. 2007;59:1210-1215.
Not in our library10.1093/jac/dkl509
265.
Sun J.R., Chan M.C., Chang T.Y., Wang W.Y., Chiueh T.S. Overexpression of the adeB gene in clinical isolates of tigecycline-nonsusceptible Acinetobacter baumannii without insertion mutations in adeRS. Antimicrob. Agents Chemother. 2010;54:4934-4938.
Not in our library10.1128/aac.00414-10
266.
Higgins P.G., Schneiders T., Hamprecht A., Seifert H. In vivo selection of a missense mutation in adeR and conversion of the novel blaOXA-164 gene into blaOXA-58 in carbapenem-resistant Acinetobacter baumannii isolates from a hospitalized patient. Antimicrob. Agents Chemother. 2010;54:5021-5027.
Not in our library10.1128/aac.00598-10
267.
Kröger C., Kary S.C., Schauer K., Cameron A.D.S. Genetic regulation of virulence and antibiotic resistance in Acinetobacter baumannii. Genes. 2016;8:12.
Not in our library10.3390/genes8010012
268.
Sun J.R., Perng C.L., Chan M.C., Morita Y., Lin J.C., Su C.M., Wang W.Y., Chang T.Y., Chiueh T.S. A truncated AdeS kinase protein generated by ISAba1 insertion correlates with tigecycline resistance in Acinetobacter baumannii. PLoS ONE. 2012;7:e49534.
Not in our library10.1371/journal.pone.0049534
269.
Sun J.R., Jeng W.Y., Perng C.L., Yang Y.S., Soo P.C., Chiang Y.S., Chiueh T.S. Single amino acid substitution Gly186Val in AdeS restores tigecycline susceptibility of Acinetobacter baumannii. J. Antimicrob. Chemother. 2016;71:1488-1492.
Not in our library10.1093/jac/dkw002
270.
Raffa R.G., Raivio T.L. A third envelope stress signal transduction pathway in Escherichia coli. Mol. Microbiol. 2002;45:1599-1611.
Not in our library10.1046/j.1365-2958.2002.03112.x
271.
Anand P., Chandra N. Characterizing the pocketome of Mycobacterium tuberculosis and application in rationalizing polypharmacological target selection. Sci. Rep. 2014;4:6356.
Not in our library10.1038/srep06356
272.
Ramakrishnan G., Chandra N.R., Srinivasan N. Recognizing drug targets using evolutionary information: Implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv. Mol. Biosyst. 2015;11:3316-3331.
Not in our library10.1039/c5mb00476d
273.
Zheng H., Aleiwi B., Ellsworth E., Abramovitch R.B. Inhibition of Mycobacterium tuberculosis DosRST two-component regulatory system signaling by targeting response regulator DNA binding and sensor kinase heme. bioRxivorg. 2018.
Not in our library10.1101/411793
274.
Stephenson K., Yamaguchi Y., Hoch J.A. The mechanism of action of inhibitors of bacterial two-component signal transduction systems. J. Biol. Chem. 2000;275:38900-38904.
Not in our library10.1074/jbc.m006633200
275.
Wilke K.E., Francis S., Carlson E.E. Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain. ACS Chem. Biol. 2015;10:328-335.
Not in our library10.1021/cb5008019
276.
Williams C., Cotter P. Autoregulation is essential for precise temporal and steady-state regulation by the Bordetella BvgAS phosphorelay. J. Bacteriol. 2007;189:1974-1982.
Not in our library10.1128/jb.01684-06
277.
Miyashiro T., Goulian M. High stimulus unmasks positive feedback in an autoregulated bacterial signaling circuit. Proc. Natl. Acad. Sci. USA. 2008;105:17457-17462.
Not in our library10.1073/pnas.0807278105
278.
Ansaldi M., Simon G., Lepelletier M., Mejean V. The TorR high-affinity binding site plays a key role in both torR autoregulation and torCAD operon expression in Escherichia coli. J. Bacteriol. 2000;182:961-966.
Not in our library10.1128/jb.182.4.961-966.2000
279.
Svenningsen S., Tu K., Bassler B. Gene dosage compensation calibrates four regulatory RNAs to control Vibrio cholerae quorum sensing. EMBO J. 2009;28:429-439.
Not in our library10.1038/emboj.2008.300
280.
Hoffer S., Westerhoff H., Hellingwerf K., Postma P., Tommassen J. Autoamplification of a two-component regulatory system results in “learning” behavior. J. Bacteriol. 2001;183:4914-4917.
Not in our library10.1128/jb.183.16.4914-4917.2001

Cited by papers we hold 3

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria · 2022
No notice
Bacterial Stress Responses as Potential Targets in Overcoming Antibiotic Resistance · 2022
No notice
The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions · 2021
Corrected

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