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The Role of Antimicrobial Peptides in Preventing Multidrug-Resistant Bacterial Infections and Biofilm Formation

Seong-Cheol Park, Yoonkyung Park, Kyung-Soo Hahm

International Journal of Molecular Sciences · 2011 · Review · CC BY

doi:10.3390/ijms12095971

Abstract

Over the last decade, decreasing effectiveness of conventional antimicrobial-drugs has caused serious problems due to the rapid emergence of multidrug-resistant pathogens. Furthermore, biofilms, which are microbial communities that cause serious chronic infections and dental plaque, form environments that enhance antimicrobial resistance. As a result, there is a continuous search to overcome or control such problems, which has resulted in antimicrobial peptides being considered as an alternative to conventional drugs. Antimicrobial peptides are ancient host defense effector molecules in living organisms. These peptides have been identified in diverse organisms and synthetically developed by using peptidomimic techniques. This review was conducted to demonstrate the mode of action by which antimicrobial peptides combat multidrug-resistant bacteria and prevent biofilm formation and to introduce clinical uses of these compounds for chronic disease, medical devices, and oral health. In addition, combinations of antimicrobial peptides and conventional drugs were considered due to their synergetic effects and low cost for therapeutic treatment.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Since penicillin was first discovered by Fleming in 1928, a large number of antibiotics have been identified, developed and clinically used in antimicrobial pharmatherapeutics. However, the widespread use of antibiotics was soon followed by the emergence of multidrug-resistant (MDR) microbes due to various reasons including abuse and the increasing use of antibiotics in the biomedical and agricultural fields. In addition to bacterial evolution, a number of patients in hospitals worldwide are currently suffering from superbugs such as vancomycin resistant enterococci (VRE), methicillin resistant Staphylococcus aureus (MRSA) and MDR bacteria. Indeed, from 1999 to 2005, the number of hospitalizations associated with MRSA infections increased by 119%, or ~14% per year. In addition, the Center for Disease Control and Prevention (CDC) reported that 1.7 million people were nosocomially infected in hospitals in 2002 and 99,000 deaths were occurring annually in the United States due to drug-resistant microbes. Moreover, as of early 2005 the number of deaths in the United Kingdom attributed to MRSA was estimated to be 3,000 per year.

Biofilms are sessile microbial communities of microbes that are adhered to various surfaces and encaged in a self-produced extracellular matrix, and have given rise to another problem in clinical therapeutics. Specifically, bacterial cells growing in a biofilm are physiologically distinct from planktonic cells of the same bacteria and are embedded within a self-produced matrix of extracelluar polymeric substance (EPS), which can increase antibiotic resistance by up to 1000 fold. Infectious processes in biofilms are related to various routes such as urinary tract and catheter infections and the formation of dental plaque. Among those, a total of 250,000 cases of catheter-associated blood stream infections that occur annually in the USA are attributed to a mortality rate of 12%~25% for each infection, with a treatment cost of $25,000 per episode.

Currently, many studies are being conducted to address the above problems, multidrug-resistant bacteria and biofilm formation. The results of these studies have led to antimicrobial peptides being considered as an alternative drug for conventional antibiotics. They have weak antimicrobial activity but potent and broad immune modulatory activity when the host organism is invaded by pathogenic microbes or viruses. Indeed many use the generic term “host defense” peptides. They do not activate adaptive immunity, but rather increase the efficiency thereof through adjuvant activity. Since antimicrobial peptides were initially identified in frogs and insects in the 1980s (for example, cecropins, PGLa, magainins), many additional peptides have been found and over 1200 have been isolated to date (http://aps.unmc.edu/AP/main.php and http://www.bbcm.units.it/~tossi/amsdb.html). Although the sequences and structures of these peptides are highly diverse, they have some common properties, including amphipathic secondary structures within membranes, a positive net charge under physiological conditions, small size, rapid binding to biological membranes, and usually the ability to kill invading microorganisms within minutes.

The mode of action of antibiotic peptides is not fully understood, but it is believed that their major targets are cytoplasmic membrane and intracellular molecules. It is also believed that it is very difficult for bacteria to develop resistance to antimicrobial peptides because most kill bacterial cells quickly through their actions on the entire cytoplasmic membrane or can act through complex mechanism. Although resistance for antimicrobial peptide has been reported, acquirement of resistance by changing the charge on surface molecules or proteolytic cleavage by the release of extracelluar protease, is limited and also takes long periods when compared to conventional drugs. Although antimicrobial peptides are much more expensive than antibiotics, many studies have found that antimicrobial peptides act effectively in synergy with currently used antibiotics against multidrug-resistant bacteria because they function through different mechanisms.

In this review, we will focus on the mode of action of antibiotics and antimicrobial peptides, their current use against multidrug-resistant bacteria, and recent findings regarding their use in the prevention of biofilms.

2. Use of AMPs in Preventing Multidrug-Resistant Bacteria

Major targets of antimicrobial peptides in bacterial cells can be divided into two cellular sites, the cell wall containing outer membrane and inner membrane and cytoplasm. Although the mechanisms inducing antibiotic-resistance are also diverse, the cellular action of antimicrobial peptides is separated from these mechanisms. For that reason, antimicrobial peptides have the potential for use in a unique antibiotic drug for combating or preventing the formation of multidrug-resistant bacteria.

2.1.1. Lipopolysaccharide (LPS) Neutralization or Disaggregation by Antimicrobial Peptides

LPSs are major components of the outer leaflet of the outer membrane in Gram-negative bacteria. LPSs consist of an O-specific chain that is highly variable in different bacterial strains, a core oligosaccharide, and lipid A. LPSs are essential for bacterial growth and viability, but macrophages stimulated by LPS induce the release of pro-inflammatory cytokines (TNF-α, IL1 and IL6) into the blood, resulting in septic shock. Accordingly, LPSs are an excellent target for antimicrobial peptides because they have the potential to both directly inhibit the growth of multidrug-resistant bacteria and to neutralize the action of released LPS due to its stimulation of immune cells.

Antimicrobial peptides generally bind to LPS through electrostatic interactions between their cationic amino acids (Lysine and Arginine) and head groups of LPS, and this complex is stabilized through hydrophobic interactions between the hydrophobic amino acids of the peptide and fatty acyl chains of LPS. Since polymyxins, which are pentabasic decapeptide antibiotics, were discovered in Bacillus polymyxa, only two have been produced commercially, polymyxin B and E (colistin). Their action, which occurs via binding to lipid A of LPS and permeabilization of the outer membrane, is restricted to Gram-negative bacteria. Sushi peptides, which are derived from Factor C (LPS-sensitive serine protease of the horseshoe crab coagulation cascade), disrupt LPS aggregates through detergent-like action and also have LPS-neutralizing activity. Moreover, even though PMAP-23, which is a porcine myeloid antibacterial peptide composed of 23 residues that adopts a helix-hinge-helix structure in membrane-mimetic environments, showed a killing activity against a broad spectrum of microbial organisms, carboxyl terminus led to growth inhibition of E. coli via the interaction with outer membrane containing LPS. Conversely, several AMPs prevent LPS-induced cytokine induction in macrophages, resulting in interruption of the development of septic shock in animal models.

Recently, the emergence of some bacteria with modifications of lipid A and LPS, such as lipid A acylation, aminoarabinose of lipid A, and myristylation of LPS which are induced by PhoP/PhoQ and PmeAB regulatory systems, has resulted in antimicrobial peptides having reduced antibacterial activity. However, this antimicrobial peptide-mediated resistance occurs when bacteria surviving in the presence of antimicrobial peptide are conducted by repeated treatments during a very long-term. Moreover, the net negative surface charge decreased by these modifications reduces the electrostatic interaction with positively charged antimicrobial peptides. Within the limits of this interaction, it is expected that this process may be overcome if other antimicrobial peptides which do not interact with LPS or possess other modes of action in bacteria were substituted.

2.2. Cell Wall-Lipid II

Cell walls of Gram-positive bacteria are formed by peptidoglycan, which are composed of polymers of sugars and amino acids outside the plasma membrane. Occasionally, inhibition of the production of peptidoglycan leads to resistance against antibiotics such as penicillin, which is inhibited via penicillin-binding proteins or transpeptidases. MRSA is also related to the existence of the penicillin-binding protein 2a (PBP2a), which is not present in susceptible S. aureus. Vancomycin resistance is caused by the production of depsipeptide d-Ala-d-Ala in the peptidoglycan. Although a number of antimicrobial peptides have been shown to be active against MRSA and VRE, in this section, we focus on antibacterial peptides with unusual amino acids, which are known as lantibiotics, because many of them exert antibacterial action through the interaction with cell wall components.

Lantibiotics are ribosomally-synthesized and post-translationally modified peptides that contain an intramolecular ring structure. These compounds are produced by Gram-positive bacteria and exert potent inhibitory action against a wide-spectrum of bacteria. These compounds are classified as either type-A or type-B, and damage the bacterial membrane and inhibit the production of enzymes, respectively. Type-A lantibiotics include nisin, subtilin, epidermin, and Pep5, while type-B include mersacidin and cinnamycin. The most well-known lantibiotic is nisin, which was isolated from Lactococcus latis and is used as a food preservative worldwide. It was initially shown that nisin forms complexes with lipid I and lipid II, and then inhibits cell wall biosynthesis. Recently, it was shown that nisin can produce short-lived pores that cause the cytoplasmic membrane to be permeable. Subtilin permeabilizes lipid membranes in a lipid II-dependent manner and binds bactoprenyl pyrophosphate. Type-B lantibiotics have been shown to inhibit the biosynthesis of cell walls by complexing lipid II, which is essential for the growth and replication of bacteria. Mersacidin does not influence the C-terminal d-Ala-d-Ala moiety of the lipid intermediate, which induces vancomycin resistance.

2.3. Alteration of Membrane Potential or Induction of Membrane Permeabilization

Two major mechanisms of multidrug-resistance are phenotypic alteration of microbes under specific growth conditions, such as biofilms, and reduction of drug accumulation into microbes through limited uptake or pumping out drugs by multidrug-resistant proteins (MDRPs). Mode of action of antimicrobial peptides in the cytoplasmic membrane is considered to be more important than other targets. Furthermore, antimicrobial peptides must permeate the cell wall and cytoplasmic membrane to reach their intracellular targets, which are nucleic acids and functional proteins.

Although the exact mechanisms of antimicrobial peptides are not fully understood, they are known to cause the efflux of intracellular materials by disrupting the cytoplasmic membrane via either pore formation through a barrel-stave or a toroidal pore mechanism, or through a nonpore carpet-like mechanism (Figure 1). In the barrel-stave model (Figure 1A), a variable number of channel-forming peptides are positioned in a barrel-like ring around an aqueous pore. Generally, the peptide, which is most likely in monomeric form, must associate with the surface of the membrane prior to insertion, and the hydrophobic region of the bound peptides is then inserted into the membrane to a depth that varies depending on the hydrophobicity of the membrane outer leaflet. When the bound peptide reaches a threshold concentration, peptide monomers self-aggregate and are inserted deeper into the hydrophobic membrane core. The hydrophobic faces of the peptides then align and face the hydrophobic lipid core region, whereas their hydrophilic faces form the interior region of a water-filled pore. This type of transmembrane pore is induced by alamethicin and ceratotoxin.

In the carpet model (Figure 1C), antimicrobial peptides accumulate on the membrane surface, where they are electrostatically bound to the anionic phospholipid head groups, carpeting the membrane surface at numerous sites. When a threshold peptide concentration is reached, membrane disruption occurs in a detergent-like manner that does not involve pore formation, and the peptides do not necessarily insert into the hydrophobic core. This model explains how cecropin P1 and caerin 1.1 disrupt membranes.

A toroidal pore model (Figure 1B) has been suggested for magainin, cathelicidin, and HPA3. In this model, antimicrobial peptides bound to the phospholipid headgroup regions of the bilayer induce a high-curvature fold in the bilayer, enabling the two leaflets of the bilayer to communicate directly at a torus lined by the leaflets. This differs from the barrel-stave model in that antimicrobial peptides are associated onto the lipid head groups even when they are perpendicularly inserted into the lipid bilayer. Recently, Han et al. directly observed magainin action on artificial vesicles using cryo-transmission electron microscopy (TEM) and an image analysis technique. They proposed that magainin-induced pores in lipid vesicles possess a mean diameter of approximately 8 nm. A pore formed by HPA3 peptide was also observed under TEM in our study. Other groups demonstrated that melittin formed a pore via the toroidal mechanism, even though it was dependent on the lipid material properties and peptide concentrations.

2.4. Inhibition of Cytoplasmic Proteins Related to Cell Division or Survival

Although most antimicrobial peptides primarily contribute to membrane perturbation, some antimicrobial peptides can penetrate the bacterial cytosol through a flip-flop mechanism or outer membrane protein forming channel. Among these, proline-rich antibacterial peptides such as pyrrhocoricin, apidaecin and drosocin have been shown to kill bacterial species by binding to the multi-helical lid region of the bacterial DnaK heat shock protein, which plays an essential role in the initiation of chromosomal DNA replication in an ATP-dependent manner with the other protein, DnaJ. The C-terminus of pyrrhocoricin was allowed to penetrate into cytosol of bacteria and the N-terminus responded to inhibit the ATPase activity of DnaK protein. Microcin B17, which is ribosomally synthesized antimicrobial peptides from Enterbacteriaceae, is also believed to inhibit DNA replication by targeting DNA gyrase.

2.5. Inhibition of Macromolecular Synthesis through Interaction with Nucleic Acids

It has been suggested that inhibition of intracellular processes by certain antimicrobial peptides that penetrate bacterial cells, such as buforin II, PR-39, indolicidin, and tPMP, may contribute to inhibition of the growth of bacterial cells or lead to cell death. Cho et al. found that buforin II, a 21-amino acid peptide derived from the Asian toad, Bufo bufo gargarizans, kills bacteria through interaction with nucleic acids without membrane permeabilization, although further investigation is needed to identify other interactions with as yet unidentified intracellular targets. PR-39, which was isolated from the small intestine of the pig, required a lag period of about 8 min to penetrate the outer membrane, after which it rapidly killed growing E. coli cells via a mechanism that stops protein and DNA synthesis. In the case of indolicidin, although it induced permeabilization of the bacterial membrane, it did not lyse the bacterial cells. Its lethal concentration allowed their filamentous morphology by inhibition of DNA synthesis in E. coli cells, and it was also found to bind specifically to DNA rather than RNA.

3. Synergetic Effects between Antimicrobial Peptides and Clinically used Antibiotics

The combined administration of antibiotics has gained interest because it often results in a synergistic antibacterial effect, which enables the dose of the individual drugs to be reduced. In addition, certain combination therapies have prevented the development of drug-resistance in bacteria. A membranolytic action of antimicrobial peptide is expected to produce synergetic effects when administered in combination with conventional antibiotics, and several studies have reported such findings. Cirioni et al. compared the synergies of magainin II and cecropin A administered with or without rifampicin against MDR Pseudomonas aeruginosa strains both in vivo and in vitro and found significant reductions in bacterial multiplication, LPS and TNF-α secretion in plasma and mortality. This finding suggested that the membrane-permeabilizing activity of peptides allows rifampicin to gain access to its intracellular target. On the other hand, synergistic effects between tachyplesin III peptide and imipenem are more effective in vivo mouse model of sepsis than in vitro study. Our research also showed that P5 peptide is synergistic in combination with isepamicin against antibiotic-resistant P. aeruginosa from patients with cholelithiasis, but not with cefpiramide. It suggested that P5 assisted penetration of isepamicin, which is an inhibitor of protein synthesis, into isepamicin-resistant strains because P5 exerted membranolytic action against bacteria. However, cefpiramide, which inhibits bacterial cell wall biosynthesis, was not synergetic. This proposed that membrane-acting peptides were effective not β-lactam but aminoglycoside antibiotics in combination due to modes of their action.

4. In Vivo Application of Antimicrobial Peptides

To data, large numbers of antimicrobial peptides have been identified in nature and designated de novo, and many of these have been confirmed to have potent antibacterial activity in vitro. However, most of clinical trials have attempted to topical applications, not to systemic applications (parenteral and oral). There are several obstacles to the use peptide therapeutic at required sites in the body through topical or oral dosing routes. These include the degradation of peptides by intestines, tissues, and serum protease and reduced half-life of small peptides through clearance by the kidneys.

Prior to the increment of circulation half-life, amino acids of antimicrobial peptide must be altered to be resistant against proteases or peptidases in serum or tissues. Many naturally isolated peptides have cationic amino acids, lysine and argine, which are easily cleaved by trypsin. Moreover, chymotrypsin and elastase, which are proteases synthesized by pancreatic acinar cells and secreted in the small intestine, are responsible for cleaving peptide bonds in hydrophobic (phenylalanine, tryptophan, and tyrosine) and small amino acids (alanine, glycine, and valine), respectively. To overcome the proteolytic cleavage of peptides, several trials have been conducted to evaluate the following: substitution of L-amino acids by d-amino acids, cyclization, conjugation of fatty acids, substitution by peptoids, use of fluorinated amino acids, beta-peptide, and acylation. As novel candidates, although lantibiotics were mostly employed in food preservation, type-B is another prospective candidate in biomedical application against infections of MDR bacteria due to its resistance to proteolytic degradation. Specifically, mersacidin has been shown to eradicate MRSA colonization in a mouse rhinitis model, and its in vivo efficacy is better against Streptococcus pyogenes than that of vancomycin.

Another problem involved in the preclinical development of antimicrobial peptides is that they are rapidly adsorbed in the kidneys during circulation due to their small size. Several strategies to extend the length of the peptides for retardation of excretion through the kidney have been proposed. One typical method is attachment of polyethylene glycol (PEG), which is widely used to prolong serum half-life. However, as with other bioactive peptides, longer PEGylation of antimicrobial peptides is unfavorable for in vitro activity, even though it enhances the circulating lifetime and decreases cytotoxicity. Despite this, shorter PEGylation was found to enable retention of the in vitro antimicrobial activity of the model peptide and improved activity in the presence of serum in an ex vivo assay when compared to unPEGylated peptide. Additionally, proteolytic degradation was reduced using this method. Nevertheless, length limitation of PEG and discovery of other methods requires further study to enable enhancement of both half-life time and antimicrobial activity in vivo prior to clinical trials.

5. Clinical Development of Antimicrobial Peptides

Several antimicrobial peptides are being evaluated in preclinical and clinical trials with limited applications. For example, Omeganan/MX-226, which is an indolicidin analogue, has recently completed phase III trials the prevention of catheter-related local and bloodstream infection, but was dropped for development. Additionally, pexiganan/MSI-78 has completed phase III clinical trials in the prevention of diabetic foot ulcers and plectasin is a fungal defensin peptide that exerts bactericidal action against drug-resistant bacteria and is currently in the preclinical phase. Opebacan, which is a human bactericidal/permeability-increasing protein derivative, has reached the phase II clinical trial for endotoxemia in hematopoetic stem cell transplant recipients. Iseganan/IB-367 from pig protegrin-1 has failed in the prevention of oral mucositis because it did not have a comparative advantage to existing therapeutics. Although several antimicrobial peptides are progressing to commercial development, records of clinical trials for antimicrobial peptides have been restricted to topical applications.

6.1. Biofilm Formation

Extended cultivation of bacterial cells results in adherence to animal tissues and inorganic materials. This, in turn, allows the formation of a biofilm, which is a multilayered community of sessile bacterial cells. Biofilms provide a survival advantage over planktonic or free-floating bacteria by enhancing nutrient trapping and colonization. Currently, biofilms are a widespread problem in hospitals and healthcare facilities. Indeed, the United States National Institutes of Health found that 80% of chronic infections are related to biofilms. Moreover, many studies have found that biofilms are associated with dental plaque, endocarditis, lung infection, and infection through medical devices.

Biofilm-formation by bacteria is achieved via responses to various factors, such as nutritional cues, cellular recognition of attachment sites on the surface, exposure to sublethal concentrations of antibiotics, and environment stresses. As shown in Figure 2, biofilm-formation is generally initiated by the attachment of planktonic cells to a surface through weak van der Waals forces (Figure 2(1)), and the colonists are anchored tightly or irreversibly by pili (Figure 2(2)). To facilitate the arrival and attachment of other planktonic cells, the initial cells construct various adhesion sites and the matrix (Figure 2(3)). Bacterial cells are then embedded within this matrix of extracelluar polymeric substance (EPS), which is composed of extracelluar DNA, proteins, lipids, and polysaccharides with various configurations. These components are very important targets for overcoming both biofilms and drug-resistant bacteria. During colonization, some bacteria can communicate through a quorum sensing (QS) system via small molecules called autoinducers and controls collective behaviors, such as bioluminescence, virulence factor production, and biofilm formation. Autoinducers in Gram-negative and -positive bacteria were known to acyl-homoserine lactone molecules and oligopeptides, respectively. It is currently considered a good target for preventing biofilm infection. Subsequently, the grown or developed biofilm provides increased antibiotic-resistance to bacterial colonies through cell division and recruitment (Figure 2(4)). Later, the developed biofilms are dispersed and the bacteria move to other surfaces, such as organs, tissues, and medical devices (Figure 2(5)), where the biofilm formation process occurs again.

6.2. Applications to Prevent or Remove Biofilms

Two main concepts in the prevention of biofilms are dispersion of the biofilm EPS and eradication of the bacteria embedded in the EPS. Typically, lethal or inhibiting concentrations of antibiotics are significantly increased by up to 1000-fold against biofilm bacteria because they are unable to translocate into EPS and therefore do not reach the bacterial cells. In contrast, antimicrobial peptides are believed to have the potential for use as anti-biofilm agents due to their different mechanisms, which include membrane-disrupting action, functional inhibition of proteins, binding with DNA, and detoxification of polysaccharides (lipopolysaccharide and lipoteichoic acid). The EPSs of biofilms contain considerable amounts of polysaccharides, proteins, nucleic acids and lipids. For example, certain antimicrobial peptides can be transferred in biofilm EPS through holes or pores formed in the lipid component of the EPS, while others can disperse biofilms.

6.2.1. In Vitro Anti-Biofilm Activity of Antimicrobial Peptides against Biofilm of MDR Bacteria

Pseudomonas aeruginosa is the significant pulmonary pathogen affecting patients with cystic fibrosis, and this organism forms a biofilm on medical devices and tissues. LL-37, a human cationic host defense peptide, showed a potent inhibitory activity in biofilm formation at a concentration of 0.5 μg/mL against P. aeruginosa biofilm and reduced pre-grown biofilms. It was also demonstrated that these effects were achieved by decreasing the attachment of bacterial cells onto the surface, stimulating twitching motility mediated by type IV pili, and down-regulating the genes related to the QS system. LL-37 also inhibited both the attachment action and development of biofilms by Staphylococcus epidermidis, being commensal in human skin and mucous membrane. Moreover, LL-37 potently inhibited the growth of planktonic cells and biofilm formation against Francisella novicida, which causes the disease tularemia. Dashper et al. reported that kappacin, nonglycosylated κ-casein (109-169), showed a significant reduction of Streptococcus mutans biofilm in the presence of ZnCl2. In addition, systematic replacement of an N-terminal amino acid with fatty acids or conjugation of fatty acids in N-terminus of synthetic short peptide leads to enhanced antibiofilm activity.

6.2.2. Anti-Biofilm Activity in Medical Devices

Recently, the beneficial effects on the survival and quality of life of patients have led to increased use of medical implants. However, medical device-related infections are often serious because contaminating bacteria on the surface of these devices can form biofilms with dense layers that are very difficult to completely remove. Currently available antibiotics fail to eradicate such infections because they are inactive in the presence of biofilms or MDR bacteria. Therefore, many researchers are suggesting that antimicrobial peptide administered alone or in combination with other molecules may be able to solve this problem.

Yoshinari et al. investigated that the adsorption of conjugated lactoferricin onto titanium surface was enhanced in the presence of hexapeptidic titanium-binding peptide and the attachment of Porphyromonas gingivalis was decreased onto this peptide-modified specimen, indicating that surface-modification with peptides can be presented as preventing method for biofilm formation on medical devices. Melimine, which is a non-hemolytic hybrid peptide between melittin and protamine, did not induce resistance against S. aureus or P. aeruginosa during repeated passage in sub-minimal inhibitory concentrations, and reduced bacterial adhesion to contact lenses to which it was covalently linked. Furthermore, silicone hydrogel lenses with melamine reduced contact lens-induced acute red eye in the P. aeruginosa guinea pig model and prevented contact lens induced peripheral ulcers in a S. aureus rabbit model. Citropin 1.1, isolated from the green tree frog Litoria citropa, has potent anti-biofilm activity and showed enhanced activity against S. aureus biofilm when administered in combination with rifampin and minocycline. The treatment of central venous catheters pre-treatedwith citropin 1.1 peptides and/or antibiotics significantly reduced bacterial counts of biofilm in a S. aureus infection rat model.

6.2.3. Anti-Biofilm Activity against Oral Plaque

Dental plaque is a complex biofilm community that forms on the teeth and oral tissues of shedding and retentive surfaces. Dental plaque develops under a variety of conditions and environments, and is composed of different bacterial species. Oral biofilms cause dental cavities and periodontal diseases, such as gingivitis and chronic periodontitis. Various therapeutic approaches have been investigated to prevent or remove oral biofilm, here we introduce the applications of antimicrobial peptides.

Gingival epithelial cells express antimicrobial peptides such as human beta-defensin-2 (hBD-2), psoriasin (S100A7), and ribonuclease 7 (RNase 7), which play important roles in innate immunity, through biofilm stimulation. Expression of these peptides can be genetically regulated on epithelial cells. Another study showed that combined treatment with chlorhexidine and bacteriocin PsVP-10 synergistically reduced the number of the biofilm-forming bacteria, Streptococcus mutans. Lactoferrin (LF) which exists in saliva and gingival crevicular fluids is related to host defense against oral pathogens. The initial attachments of Streptococcus gordonii and S. mutans forming biofilm in oral cavity were inhibited in the presence of LF. It was recently investigated that LF was able to inhibit planktonic growth of Porphyromonas gingivalis and Prevotella intermedia, which make biofilm in the subgingival plaque, and to suppress biofilm formation at a low concentration (≥8 μg/mL). LF alone or in combination with antibiotics also showed a reduction of pre-forming biofilm. Moreover, in small-scale clinical trial, patients administered a tablet with 0.3 g of bovine LF for 3 months had an effect on reduction of bacterial numbers in the subgingival plaque. Leung et al. proposed an interesting approach in which a chewing gum containing both KSL-W synthetic peptide and cetylpyridinium chloride displayed a dose-dependent reduction against a biofilm of human salivary bacteria. Gum formulation with this combination was proposed to be used as an antiplaque agent or adjunct for oral hygiene.

6.2.4. Others

Another approach to inhibiting biofilm formation is the use enzymes that can degrade the EPS of biofilm and detach established biofilm colonies. Moreover, biofilm-dispersing enzymes administered in combination treatment with antimicrobial agents will allow them to kill bacteria embedded in EPS. Kaplan et al. suggested that deoxyribonuclease I and glycoside hydrolase dispersin B are useful as anti-biofilm agents due to the dispersing action of EPS layers on medical devices. In addition, therapeutic treatment of combination treatments with antimicrobial peptides may result in significant synergetic-effects against MDR bacteria and the formation of biofilms.

8. Conclusions

Antimicrobial peptides can be the next generation of antibiotics for combating multi-drug resistant and/or biofilm forming bacterial infections. These peptides have a strong potential for application as nanofilms or other coating materials for surgical devices, including catheters. Even though there are drawbacks to the use of peptides as therapeutics, such as low bioavailability and high cost, these obstacles may be overcome since a great deal of effort is being conducted to circumvent the problems associated with various methods including the use of d- or unnatural amino acid, formulation, recombinant DNA expression of peptides, addition of fatty acyl chains to short peptides. Therefore, it is expected that antimicrobial peptides will become the drugs of choice for emerging bacterial infections in the future.

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    Mukhopadhyay K, Whitmire W, Xiong YQ, Molden J, Jones T, Peschel A, Staubitz P, Adler-Moore J, McNamara PJ, Proctor RA, Yeaman MR, Bayer AS. In vitro susceptibility of Staphylococcus aureus to thrombin-induced platelet microbicidal protein-1 (tPMP-1) is influenced by cell membrane phospholipid composition and asymmetry. Microbiology. 2007;153:1187-1197.

    Not in our library10.1099/mic.0.2006/003111-0

  23. 23.

    Thwaite JE, Hibbs S, Titball RW, Atkins TP. Proteolytic degradation of human antimicrobial peptide LL-37 by Bacillus anthracis may contribute to virulence. Antimicrob Agents Chemother. 2006;50:2316-2322.

    Not in our library10.1128/aac.01488-05

  24. 24.

    McGillivray SM, Ebrahimi CM, Fisher N, Sabet M, Zhang DX, Chen Y, Haste NM, Aroian RV, Gallo RL, Guiney DG, Friedlander AM, Koehler TM, Nizet V. ClpX contributes to innate defense peptide resistance and virulence phenotypes of Bacillus anthracis. J Innate Immun. 2009;1:494-506.

    Not in our library10.1159/000225955

  25. 25.

    Giacometti A, Cirioni O, Kamysz W, D’Amato G, Silvestri C, Simona Del Prete M, Lukasiak J, Scalise G. In vitro activity and killing effect of the synthetic hybrid cecropin A-melittin peptide CA(1-7)M(2-9)NH(2) on methicillin-resistant nosocomial isolates of Staphylococcus aureus and interactions with clinically used antibiotics. Diagn Microbiol Infect Dis. 2004;49:197-200.

    Not in our library10.1016/j.diagmicrobio.2004.02.008

  26. 26.

    Park Y, Park SN, Park SC, Shin SO, Kim JY, Kang SJ, Kim MH, Jeong CY, Hahm KS. Synergism of Leu-Lys rich antimicrobial peptides and chloramphenicol against bacterial cells. Biochim Biophys Acta. 2006;1764:24-32.

    Not in our library10.1016/j.bbapap.2005.10.019

  27. 27.

    Park Y, Kim HJ, Hahm KS. Antibacterial synergism of novel antibiotic peptides with chloramphenicol. Biochem Biophys Res Commun. 2004;321:109-115.

    Not in our library10.1016/j.bbrc.2004.06.113

  28. 28.

    Gutsmann T, Hagge SO, David A, Roes S, Böhling A, Hammer MU, Seydel U. Lipid-mediated resistance of Gram-negative bacteria against various pore-forming antimicrobial peptides. J Endotoxin Res. 2005;11:167-173.

    Not in our library10.1179/096805105x37330

  29. 29.

    Gee K, Kozlowski M, Kumar A. Tumor necrosis factor-alpha induces functionally active hyaluronan-adhesive CD44 by activating sialidase through p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated human monocytic cells. J Biol Chem. 2003;278:37275-37287.

    Not in our library10.1074/jbc.m302309200

  30. 30.

    Blanqué R, Meakin C, Millet S, Gardner CR. Hypothermia as an indicator of the acute effects of lipopolysaccharides: Comparison with serum levels of IL1 beta, IL6 and TNF alpha. Gen Pharmacol. 1996;27:973-977.

    Not in our library10.1016/0306-3623(95)02141-8

  31. 31.

    Freudenberg MA, Tchaptchet S, Keck S, Fejer G, Huber M, Schütze N, Beutler B, Galanos C. Lipopolysaccharide sensing an important factor in the innate immune response to Gram-negative bacterial infections: Benefits and hazards of LPS hypersensitivity. Immunobiology. 2008;213:193-203.

    Not in our library10.1016/j.imbio.2007.11.008

  32. 32.

    Li P, Wohland T, Ho B, Ding JL. Perturbation of Lipopolysaccharide (LPS) Micelles by Sushi 3 (S3) antimicrobial peptide. The importance of an intermolecular disulfide bond in S3 dimer for binding, disruption, and neutralization of LPS. J Biol Chem. 2004;279:50150-50156.

    Not in our library10.1074/jbc.m405606200

  33. 33.

    Bhattacharjya S, Domadia PN, Bhunia A, Malladi S, David SA. High-resolution solution structure of a designed peptide bound to lipopolysaccharide: transferred nuclear overhauser effects, micelle selectivity, and anti-endotoxic activity. Biochemistry. 2007;46:5864-5874.

    Not in our library10.1021/bi6025159

  34. 34.

    Storm DR, Rosental KS, Swanson PE. Polymyxin and related peptide antibiotics. Annu Rev Biochem. 1977;46:723-763.

    Not in our library10.1146/annurev.bi.46.070177.003451

  35. 35.

    Kwa A, Kasiakou SK, Tam VH, Falagas ME. Polymyxin B: Similarities to and differences from colistin (polymyxin E). Expert Rev Anti-Infect Ther. 2007;5:811-821.

    Not in our library10.1586/14787210.5.5.811

  36. 36.

    Mogi T, Kita K. Gramicidin S and polymyxins: The revival of cationic cyclic peptide antibiotics. Cell Mol Life Sci. 2007;66:3821-3826.

    Not in our library10.1007/s00018-009-0129-9

  37. 37.

    Ding JL, Li P, Ho B. The Sushi peptides: structural characterization and mode of action against Gram-negative bacteria. Cell Mol Life Sci. 2008;65:1202-1219.

    Not in our library10.1007/s00018-008-7456-0

  38. 38.

    Kim JY, Park SC, Yoon MY, Hahm KS, Park Y. C-terminal amidation of PMAP-23: Translocation to the inner membrane of Gram-negative bacteria. Amino Acids. 2011;40:183-195.

    Not in our library10.1007/s00726-010-0632-1

  39. 39.

    Gough M, Hancock RE, Kelly NM. Antiendotoxin activity of cationic peptide antimicrobial agents. Infect Immun. 1996;64:4922-4927.

    Not in our library10.1128/iai.64.12.4922-4927.1996

  40. 40.

    Scott MG, Yan H, Hancock RE. Biological properties of structurally related alpha-helical cationic antimicrobial peptides. Infect Immun. 1999;67:2005-2009.

    Not in our library10.1128/iai.67.4.2005-2009.1999

  41. 41.

    Giacometti A, Cirioni O, Ghiselli R, Mocchegiani F, Del Prete MS, Viticchi C, Kamysz W, Lempicka E, Saba V, Scalise G. Potential therapeutic role of cationic peptides in three experimental models of septic shock. Antimicrob Agents Chemother. 2002;46:2132-2136.

    Not in our library10.1128/aac.46.7.2132-2136.2002

  42. 42.

    Guo L, Lim KB, Poduje CM, Daniel M, Gunn JS, Hackett M, Miller SI. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell. 1998;95:189-198.

    Not in our library10.1016/s0092-8674(00)81750-x

  43. 43.

    Zhou Z, Lin S, Cotter RJ, Raetz CR. Lipid A modifications characteristic of Salmonella typhimurium are induced by NH4VO3 in Escherichia coli K12. Detection of 4-amino-4-deoxy-l-arabinose, phosphoethanolamine and palmitate. J Biol Chem. 1999;274:18503-18514.

    Not in our library10.1074/jbc.274.26.18503

  44. 44.

    Ernst RK, Guina T, Miller SI. How intracellular bacteria survive: surface modifications that promote resistance to host innate immune responses. J Infect Dis. 1999;179:S326-S330.

    Not in our library10.1086/513850

  45. 45.

    Glaser L. Bacterial cell surface polysaccharides. Annu Rev Biochem. 1973;42:91-112.

    Not in our library10.1146/annurev.bi.42.070173.000515

  46. 46.

    Di Guilmi AM, Dessen A, Dideberg O, Vernet T. Bifunctional penicillin-binding proteins: Focus on the glycosyltransferase domain and its specific inhibitor moenomycin. Curr Pharm Biotechnol. 2002;3:63-75.

    Not in our library10.2174/1389201023378436

  47. 47.

    Wilke MS, Lovering AL, Strynadka NC. Beta-lactam antibiotic resistance: a current structural perspective. Curr Opin Microbiol. 2005;8:525-533.

    Not in our library10.1016/j.mib.2005.08.016

  48. 48.

    Brakstad OG, Maeland JA. Mechanisms of methicillin resistance in staphylococci. APMIS. 1997;105:264-276.

    Not in our library10.1111/j.1699-0463.1997.tb00568.x

  49. 49.

    Berger-Bächi B, Rohrer S. Factors influencing methicillin resistance in staphylococci. Arch Microbiol. 2002;178:165-171.

    Not in our library10.1007/s00203-002-0436-0

  50. 50.

    Gin AS, Zhanel GG. Vancomycin-resistant enterococci. Ann Pharmacother. 1996;30:615-624.

    Not in our library10.1177/106002809603000610

  51. 51.

    Bierbaum G, Sahl HG. Lantibiotics: Mode of action, biosynthesis and bioengineering. Curr Pharm Biotechnol. 2009;10:2-18.

    Not in our library10.2174/138920109787048616

  52. 52.

    Mattick AT, Hirsch A. Further observations on an inhibitory substance (nisin) from lactic streptococci. Lancet. 1947;2:5-8.

    Not in our library10.1016/s0140-6736(47)90004-4

  53. 53.

    Jansen EF, Hirschmann DJ. Binding of simple carbohydrates and some N-acetyllactosamine-containing oligosaccharides to Erythrina cristagalli agglutinin as followed with a fluorescent indicator ligand. Arch Biochem. 1994;4:297-304.

    Not in our library10.1016/0003-9861(84)90352-7

  54. 54.

    Allgaier H, Jung G, Werner RG, Schneider U, Zähner H. Epidermin: sequencing of a heterodetic tetracyclic 21-peptide amide antibiotic. Eur J Biochem. 1986;160:9-22.

    Not in our library10.1111/j.1432-1033.1986.tb09933.x

  55. 55.

    Sahl HG, Grossgarten M, Widger WR, Cramer WA, Brandis H. Structural similarities of the staphylococcin-like peptide Pep-5 to the peptide antibiotic nisin. Antimicrob Agents Chemother. 1985;27:836-840.

    Not in our library10.1128/aac.27.5.836

  56. 56.

    Chatterjee S, Chatterjee S, Lad SJ, Phansalkar MS, Rupp RH, Ganguli BN, Fehlhaber HW, Kogler H. Mersacidin, a new antibiotic from Bacillus. Fermentation, isolation, purification and chemical characterization. J Antibiot. 1992;45:832-838.

    Not in our library10.7164/antibiotics.45.832

  57. 57.

    Fredenhagen A, Fendrich G, Märki F, Märki W, Gruner J, Raschdorf F, Peter HH. Duramycins B and C, two new lanthionine containing antibiotics as inhibitors of phospholipase A2. Structural revision of duramycin and cinnamycin. J Antibiot. 1990;43:1403-1412.

    Not in our library10.7164/antibiotics.43.1403

  58. 58.

    Hansen JN. Nisin as a model food preservative. Crit Rev Food Sci Nutr. 1994;34:69-93.

    Not in our library10.1080/10408399409527650

  59. 59.

    Hasper HE, Kramer NE, Smith JL, Hillman JD, Zachariah C, Kuipers OP, de Kruijff B, Breukink E. An alternative bactericidal mechanism of action for lantibiotic peptides that target lipid II. Science. 2006;313:1636-1637.

    Not in our library10.1126/science.1129818

  60. 60.

    Bierbaum G, Sahl HG. Lantibiotics: Mode of action, biosynthesis and bioengineering. Curr Pharm Biotechnol. 2009;10:2-18.

    Not in our library10.2174/138920109787048616

  61. 61.

    Hsu ST, Breukink E, Tischenko E, Lutters MA, de Kruijff B, Kaptein R, Bonvin AM, van Nuland NA. The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nat Struct Mol Biol. 2004;11:963-967.

    Not in our library10.1038/nsmb830

  62. 62.

    Parisot J, Carey S, Breukink E, Chan WC, Narbad A, Bonev B. Molecular mechanism of target recognition by subtilin, a class I lanthionine antibiotic. Antimicrob Agents Chemother. 2008;52:612-618.

    Not in our library10.1128/aac.00836-07

  63. 63.

    Sahl HG, Jack RW, Bierbaum G. Biosynthesis and biological activities of lantibiotics with unique post-translational modifications. Eur J Biochem. 1995;230:827-853.

    Not in our library10.1111/j.1432-1033.1995.tb20627.x

  64. 64.

    Brötz H, Bierbaum G, Leopold K, Reynolds PE, Sahl HG. The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II. Antimicrob Agents Chemother. 1998;42:154-160.

    Not in our library10.1128/aac.42.1.154

  65. 65.

    Alibert-Franco S, Pradines B, Mahamoud A, Davin-Regli A, Pagès JM. Efflux mechanism, an attractive target to combat multidrug resistant Plasmodium falciparum and Pseudomonas aeruginosa. Curr Med Chem. 2009;16:301-317.

    Not in our library10.2174/092986709787002619

  66. 66.

    Langton KP, Henderson PJ, Herbert RB. Antibiotic resistance: Multidrug efflux proteins, a common transport mechanism? Nat Prod Rep. 2005;22:439-451.

    Not in our library10.1039/b413734p

  67. 67.

    Zgurskaya HI, Krishnamoorthy G, Tikhonova EB, Lau SY, Stratton KL. Mechanism of antibiotic efflux in Gram-negative bacteria. Front Biosci. 2003;8:s862-s873.

    Not in our library10.2741/1134

  68. 68.

    Pérez A, Canle D, Latasa C, Poza M, Beceiro A, Tomás Mdel M, Fernández A, Mallo S, Pérez S, Molina F, et al. Cloning, nucleotide sequencing, and analysis of the AcrAB-TolC efflux pump of Enterobacter cloacae and determination of its involvement in antibiotic resistance in a clinical isolate. Antimicrob Agents Chemother. 2007;51:3247-3253.

    Not in our library10.1128/aac.00072-07

  69. 69.

    Nicolas P. Multifunctional host defense peptides: Intracellular-targeting antimicrobial peptides. FEBS J. 2009;276:6483-6496.

    Not in our library10.1111/j.1742-4658.2009.07359.x

  70. 70.

    Oren Z, Shai Y. Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers. 1998;47:451-463.

    Not in our library10.1002/(sici)1097-0282(1998)47:6<451::aid-bip4>3.0.co;2-f

  71. 71.

    Mihajlovic M, Lazaridis T. Antimicrobial peptides in toroidal and cylindrical pores. Biochim Biophys Acta. 2010;1798:1485-1493.

    Not in our library10.1016/j.bbamem.2010.04.004

  72. 72.

    Gottler LM, Ramamoorthy A. Structure, membrane orientation, mechanism, and function of pexiganan--a highly potent antimicrobial peptide designed from magainin. Biochim Biophys Acta. 2009;1788:1680-1686.

    Not in our library10.1016/j.bbamem.2008.10.009

  73. 73.

    Shai Y, Oren Z. From “carpet” mechanism to de-novo designed diastereomeric cell-selective antimicrobial peptides. Peptides. 2001;22:1629-1641.

    Not in our library10.1016/s0196-9781(01)00498-3

  74. 74.

    Ramamoorthy A, Lee DK, Narasimhaswamy T, Nanga RP. Cholesterol reduces pardaxin’s dynamics-a barrel-stave mechanism of membrane disruption investigated by solid-state NMR. Biochim Biophys Acta. 2010;1798:223-227.

    Not in our library10.1016/j.bbamem.2009.08.012

  75. 75.

    Cantor RS. Size distribution of barrel-stave aggregates of membrane peptides: Influence of the bilayer lateral pressure profile. Biophys J. 2002;82:2520-2525.

    Not in our library10.1016/s0006-3495(02)75595-1

  76. 76.

    Bessin Y, Saint N, Marri L, Marchini D, Molle G. Antibacterial activity and pore-forming properties of ceratotoxins: A mechanism of action based on the barrel stave model. Biochim Biophys Acta. 2004;1667:148-156.

    Not in our library10.1016/j.bbamem.2004.09.011

  77. 77.

    Gazit E, Miller IR, Biggin PC, Sansom MS, Shai Y. Structure and orientation of the mammalian antibacterial peptide cecropin P1 within phospholipid membranes. J Mol Biol. 1996;258:860-870.

    Not in our library10.1006/jmbi.1996.0293

  78. 78.

    Wong H, Bowie JH, Carver JA. The solution structure and activity of caerin 1.1, an antimicrobial peptide from the Australian green tree frog, Litoria splendida. Eur J Biochem. 1997;247:545-557.

    Not in our library10.1111/j.1432-1033.1997.00545.x

  79. 79.

    Ludtke SJ, He K, Heller WT, Harroun TA, Yang L, Huang HW. Membrane pores induced by magainin. Biochemistry. 1996;35:13723-13728.

    Not in our library10.1021/bi9620621

  80. 80.

    Tamba Y, Yamazaki M. Magainin 2-induced pore formation in the lipid membranes depends on its concentration in the membrane interface. J Phys Chem B. 2009;113:4846-4852.

    Not in our library10.1021/jp8109622

  81. 81.

    Basanez G, Shinnar AE, Zimmerberg J. Interaction of hagfish cathelicidin antimicrobial peptides with model lipid membranes. FEBS Lett. 2002;532:115-120.

    Not in our library10.1016/s0014-5793(02)03651-7

  82. 82.

    Henzler Wildman KA, Lee DK, Ramamoorthy A. Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37. Biochemistry. 2003;42:6545-6558.

    Not in our library10.1021/bi0273563

  83. 83.

    Park SC, Kim MH, Hossain MA, Shin SY, Kim Y, Stella L, Wade JD, Park Y, Hahm KS. Amphipathic alpha-helical peptide, HP (2-20), and its analogues derived from Helicobacter pylori: Pore formation mechanism in various lipid compositions. Biochim Biophys Acta. 2008;1778:229-241.

    Not in our library10.1016/j.bbamem.2007.09.020

  84. 84.

    Lee TH, Hall KN, Swann MJ, Popplewell JF, Unabia S, Park Y, Hahm KS, Aguilar MI. The membrane insertion of helical antimicrobial peptides from the N-terminus of Helicobacter pylori ribosomal protein L1. Biochim Biophys Acta. 2010;1798:544-557.

    Not in our library10.1016/j.bbamem.2010.01.014

  85. 85.

    Park SC, Kim JY, Shin SO, Jeong CY, Kim MH, Shin SY, Cheong GW, Park Y, Hahm KS. Investigation of toroidal pore and oligomerization by melittin using transmission electron microscopy. Biochem Biophys Res Commun. 2006;343:222-228.

    Not in our library10.1016/j.bbrc.2006.02.090

  86. 86.

    Han M, Mei Y, Khant H, Ludtke SJ. Characterization of antibiotic peptide pores using cryo-EM and comparison to neutron scattering. Biophys J. 2009;97:164-172.

    Not in our library10.1016/j.bpj.2009.04.039

  87. 87.

    Yang L, Harroun TA, Weiss TM, Ding L, Huang HW. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J. 2001;81:1475-1485.

    Not in our library10.1016/s0006-3495(01)75802-x

  88. 88.

    Allende D, Simon SA, McIntosh TJ. Melittin-induced bilayer leakage depends on lipid material properties: evidence for toroidal pores. Biophys J. 2005;88:1828-1837.

    Not in our library10.1529/biophysj.104.049817

  89. 89.

    Kragol G, Hoffmann R, Chattergoon MA, Lovas S, Cudic M, Bulet P, Condie BA, Rosengren KJ, Montaner LJ, Otvos L. Identification of crucial residues for the antibacterial activity of the proline-rich peptide, pyrrhocoricin. Eur J Biochem. 2002;269:4226-4237.

    Not in our library10.1046/j.1432-1033.2002.03119.x

  90. 90.

    Kragol G, Lovas S, Varadi G, Condie BA, Hoffmann R, Otvos L. The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry. 2001;40:3016-3026.

    Not in our library10.1021/bi002656a

  91. 91.

    Otvos L, Insug O, Rogers ME, Consolvo PJ, Condie BA, Lovas S, Bulet P, Blaszczyk-Thurin M. Interaction between heat shock proteins and antimicrobial peptides. Biochemistry. 2000;39:14150-14159.

    Not in our library10.1021/bi0012843

  92. 92.

    Vizan JL, Hernández-Chico C, del Castillo I, Moreno F. The peptide antibiotic microcin B17 induces double-strand cleavage of DNA mediated by E. coli DNA gyrase. EMBO J. 1991;10:467-476.

    Not in our library10.1002/j.1460-2075.1991.tb07969.x

  93. 93.

    Park CB, Kim HS, Kim SC. Mechanism of action of the antimicrobial peptide buforin II: Buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochem Biophys Res Commun. 1998;244:253-257.

    Not in our library10.1006/bbrc.1998.8159

  94. 94.

    Boman HG, Agerberth B, Boman A. Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine. Infect Immun. 1993;61:2978-2984.

    Not in our library10.1128/iai.61.7.2978-2984.1993

  95. 95.

    Subbalakshmi C, Sitaram N. Mechanism of antimicrobial action of indolicidin. FEMS Microbiol Lett. 1998;160:91-96.

    Not in our library10.1111/j.1574-6968.1998.tb12896.x

  96. 96.

    Xiong YQ, Bayer AS, Yeaman MR. Inhibition of intracellular macromolecular synthesis in Staphylococcus aureus by thrombin-induced platelet microbicidal proteins. J Infect Dis. 2002;185:348-356.

    Not in our library10.1086/338514

  97. 97.

    Cho JH, Sung BH, Kim SC. Buforins: histone H2A-derived antimicrobial peptides from toad stomach. Biochim Biophys Acta. 2009;1788:1564-1569.

    Not in our library10.1016/j.bbamem.2008.10.025

  98. 98.

    Hsu CH, Chen C, Jou ML, Lee AY, Lin YC, Yu YP, Huang WT, Wu SH. Structural and DNA-binding studies on the bovine antimicrobial peptide, indolicidin: Evidence for multiple conformations involved in binding to membranes and DNA. Nucleic Acids Res. 2005;33:4053-4064.

    Not in our library10.1093/nar/gki725

  99. 99.

    Barriere SL. Bacterial resistance to beta-lactams, and its prevention with combination antimicrobial therapy. Pharmacotherapy. 1992;12:397-402.

    Not in our library

  100. 100.

    Wu YL, Scott EM, Po AL, Tariq VN. Ability of azlocillin and tobramycin in combination to delay or prevent resistance development in Pseudomonas aeruginosa. J Antimicrob Chemother. 1999;44:389-392.

    Not in our library10.1093/jac/44.3.389

  101. 101.

    Steenbergen JN, Mohr JF, Thorne GM. Effects of daptomycin in combination with other antimicrobial agents: A review of in vitro and animal model studies. J Antimicrob Chemother. 2009;64:1130-1138.

    Not in our library10.1093/jac/dkp346

  102. 102.

    Anantharaman A, Rizvi MS, Sahal D. Synergy with rifampin and kanamycin enhances potency, kill kinetics, and selectivity of de novo-designed antimicrobial peptides. Antimicrob Agents Chemother. 2010;54:1693-1699.

    Not in our library10.1128/aac.01231-09

  103. 103.

    Cirioni O, Silvestri C, Ghiselli R, Orlando F, Riva A, Mocchegiani F, Chiodi L, Castelletti S, Gabrielli E, Saba V, et al. Protective effects of the combination of alpha-helical antimicrobial peptides and rifampicin in three rat models of Pseudomonas aeruginosa infection. J Antimicrob Chemother. 2008;62:1332-1338.

    Not in our library10.1093/jac/dkn393

  104. 104.

    Cirioni O, Ghiselli R, Silvestri C, Kamysz W, Orlando F, Mocchegiani F, Di Matteo F, Riva A, Lukasiak J, Scalise G, et al. Efficacy of tachyplesin III, colistin, and imipenem against a multiresistant Pseudomonas aeruginosa strain. Antimicrob Agents Chemother. 2007;51:2005-2010.

    Not in our library10.1128/aac.01576-06

  105. 105.

    Jeong N, Kim JY, Park SC, Lee JK, Gopal R, Yoo S, Son BK, Hahm JS, Park Y, Hahm KS. Antibiotic and synergistic effect of Leu-Lys rich peptide against antibiotic resistant microorganisms isolated from patients with cholelithiasis. Biochem Biophys Res Commun. 2010;399:581-586.

    Not in our library10.1016/j.bbrc.2010.07.118

  106. 106.

    McGregor DP. Discovering and improving novel peptide therapeutics. Curr Opin Pharmacol. 2008;8:616-619.

    Not in our library10.1016/j.coph.2008.06.002

  107. 107.

    Svenson J, Stensen W, Brandsdal BO, Haug BE, Monrad J, Svendsen JS. Antimicrobial peptides with stability toward tryptic degradation. Biochemistry. 2008;47:3777-3788.

    Not in our library10.1021/bi7019904

  108. 108.

    Park KH, Nan YH, Park Y, Kim JI, Park IS, Hahm KS, Shin SY. Cell specificity, anti-inflammatory activity, and plausible bactericidal mechanism of designed Trp-rich model antimicrobial peptides. Biochim Biophys Acta. 2009;1788:1193-1203.

    Not in our library10.1016/j.bbamem.2009.02.020

  109. 109.

    Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci. 2007;52:1-17.

    Not in our library10.1007/s10620-006-9589-z

  110. 110.

    Gray GM, Cooper HL. Protein digestion and absorption. Gastroenterology. 1971;61:535-544.

    Not in our library

  111. 111.

    Park Y, Park SC, Kim JY, Park JO, Seo CH, Nah JW, Hahm KS. In vitro efficacy of a synthetic all-d antimicrobial peptide against clinically isolated drug-resistant strains. Int J Antimicrob Agents. 2010;35:208-209.

    Not in our library10.1016/j.ijantimicag.2009.10.010

  112. 112.

    Wang P, Nan YH, Yang ST, Kang SW, Kim Y, Park IS, Hahm KS, Shin SY. Cell selectivity and anti-inflammatory activity of a Leu/Lys-rich alpha-helical model antimicrobial peptide and its diastereomeric peptides. Peptides. 2010;31:1251-1261.

    Not in our library10.1016/j.peptides.2010.03.032

  113. 113.

    Dartois V, Sanchez-Quesada J, Cabezas E, Chi E, Dubbelde C, Dunn C, Granja J, Gritzen C, Weinberger D, Ghadiri MR, et al. Systemic antibacterial activity of novel synthetic cyclic peptides. Antimicrob Agents Chemother. 2005;49:3302-3310.

    Not in our library10.1128/aac.49.8.3302-3310.2005

  114. 114.

    Rozek A, Powers JP, Friedrich CL, Hancock RE. Structure-based design of an indolicidin peptide analogue with increased protease stability. Biochemistry. 2003;42:14130-14138.

    Not in our library10.1021/bi035643g

  115. 115.

    Avrahami D, Shai Y. Conjugation of a magainin analogue with lipophilic acids controls hydrophobicity, solution assembly, and cell selectivity. Biochemistry. 2002;41:2254-2263.

    Not in our library10.1021/bi011549t

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    Chongsiriwatana NP, Patch JA, Czyzewski AM, Dohm MT, Ivankin A, Gidalevitz D, Zuckermann RN, Barron AE. Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides. Proc Natl Acad Sci USA. 2008;105:2794-2799.

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    Wang P, Bang JK, Kim HJ, Kim JK, Kim Y, Shin SY. Antimicrobial specificity and mechanism of action of disulfide-removed linear analogs of the plant-derived Cys-rich antimicrobial peptide Ib-AMP1. Peptides. 2009;30:2144-2149.

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    Meng H, Kumar K. Antimicrobial activity and protease stability of peptides containing fluorinated amino acids. J Am Chem Soc. 2007;129:15615-15622.

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    Porter EA, Weisblum B, Gellman SH. Mimicry of host-defense peptides by unnatural oligomers: antimicrobial beta-peptides. J Am Chem Soc. 2002;124:7324-7330.

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    Radzishevsky IS, Rotem S, Bourdetsky D, Navon-Venezia S, Carmeli Y, Mor A. Improved antimicrobial peptides based on acyl-lysine oligomers. Nat Biotechnol. 2007;25:657-659.

    Not in our library10.1038/nbt1309

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    Kruszewska D, Sahl HG, Bierbaum G, Pag U, Hynes SO, Ljungh A. Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model. J Antimicrob Chemother. 2004;54:648-653.

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    Chatterjee S, Chatterjee DK, Jani RH, Blumbach J, Ganguli BN, Klesel N, Limbert M, Seibert G. Mersacidin, a new antibiotic from Bacillus. In vitro and in vivo antibacterial activity. J Antibiot (Tokyo). 1992;45:839-845.

    Not in our library10.7164/antibiotics.45.839

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    Jevsevar S, Kunstelj M, Porekar VG. PEGylation of therapeutic proteins. Biotechnol J. 2010;5:113-128.

    Not in our library10.1002/biot.200900218

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    Pasut G, Veronese FM. PEG conjugates in clinical development or use as anticancer agents: An overview. Adv Drug Deliv Rev. 2009;61:1177-1188.

    Not in our library10.1016/j.addr.2009.02.010

  125. 125.

    Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs. 2008;22:315-329.

    Not in our library10.2165/00063030-200822050-00004

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    Imura Y, Nishida M, Ogawa Y, Takakura Y, Matsuzaki K. Action mechanism of tachyplesin I and effects of PEGylation. Biochim Biophys Acta. 2007;1768:1160-1169.

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    Imura Y, Nishida M, Matsuzaki K. Action mechanism of PEGylated magainin 2 analogue peptide. Biochim Biophys Acta. 2007;1768:2578-2585.

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    Zhang G, Han B, Lin X, Wu X, Yan H. Modification of antimicrobial peptide with low molar mass poly(ethylene glycol). J Biochem. 2008;144:781-788.

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  129. 129.

    Isaacson RE. MBI-226. Micrologix/Fujisawa. Curr Opin Investig Drugs. 2003;4:999-1003.

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  130. 130.

    Rubinchik E, Dugourd D, Algara T, Pasetka C, Friedland HD. Antimicrobial and antifungal activities of a novel cationic antimicrobial peptide, omiganan, in experimental skin colonisation models. Int J Antimicrob Agents. 2009;34:457-461.

    Not in our library10.1016/j.ijantimicag.2009.05.003

  131. 131.

    Yeung AT, Gellatly SL, Hancock RE. Multifunctional cationic host defence peptides and their clinical applications. Cell Mol Life Sci. 2011;68:2161-2176.

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    Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006;24:1551-1557.

    Not in our library10.1038/nbt1267

  133. 133.

    Zaiou M. Multifunctional antimicrobial peptides: Therapeutic targets in several human diseases. J Mol Med. 2007;85:317-329.

    Not in our library10.1007/s00109-006-0143-4

  134. 134.

    Zhang L, Falla TJ. Antimicrobial peptides: Therapeutic potential. Expert Opin Pharmacother. 2006;7:653-663.

    Not in our library10.1517/14656566.7.6.653

  135. 135.

    Costerton JW, Irvin RT, Cheng KJ. The bacterial glycocalyx in nature and disease. Ann Rev Microbiol. 1981;35:299-324.

    Not in our library10.1146/annurev.mi.35.100181.001503

  136. 136.

    Costerton J. Introduction to biofilm. Int J Antimicrob Agents. 1999;11:217-221.

    Not in our library10.1016/s0924-8579(99)00018-7

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    Hojo K, Nagaoka S, Ohshima T, Maeda N. Bacterial interactions in dental biofilm development. J Dent Res. 2009;88:982-990.

    Not in our library10.1177/0022034509346811

  138. 138.

    Paju S, Scannapieco FA. Oral biofilms, periodontitis, and pulmonary infections. Oral Dis. 2007;13:508-512.

    Not in our library10.1111/j.1601-0825.2007.1410a.x

  139. 139.

    Palmer J. Bacterial biofilms in chronic rhinosinusitis. Ann Otol Rhinol Laryngol Suppl. 2006;196:35-39.

    Not in our library10.1177/00034894061150s906

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    Wagner VE, Iglewski BH. P. aeruginosa Biofilms in CF Infection. Clin Rev Allergy Immunol. 2008;35:124-134.

    Not in our library10.1007/s12016-008-8079-9

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    Lau GW, Hassett DJ, Britigan BE. Modulation of lung epithelial functions by Pseudomonas aeruginosa. Trends Microbiol. 2005;13:389-397.

    Not in our library10.1016/j.tim.2005.05.011

  142. 142.

    Khardori N, Yassien M. Biofilms in device-related infections. J Ind Microbiol. 1995;15:141-147.

    Not in our library10.1007/bf01569817

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    Habash M, Reid G. Microbial biofilms: their development and significance for medical device-related infections. J Clin Pharmacol. 1999;39:887-898.

    Not in our library10.1177/00912709922008506

  144. 144.

    Hoffman LR, D’Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller SI. Aminoglycoside antibiotics induce bacterial biofilm formation. Nature. 2005;436:1171-1175.

    Not in our library10.1038/nature03912

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    Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999;284:1318-1322.

    Not in our library10.1126/science.284.5418.1318

  146. 146.

    Hall-Stoodley L, Stoodley P. Evolving concepts in biofilm infections. Cell Microbiol. 2009;11:1034-1043.

    Not in our library10.1111/j.1462-5822.2009.01323.x

  147. 147.

    Landini P, Antoniani D, Burgess JG, Nijland R. Molecular mechanisms of compounds affecting bacterial biofilm formation and dispersal. Appl Microbiol Biotechnol. 2010;86:813-823.

    Not in our library10.1007/s00253-010-2468-8

  148. 148.

    Horswill AR, Stoodley P, Stewart PS, Parsek MR. The effect of the chemical, biological, and physical environment on quorum sensing in structured microbial communities. Anal Bioanal Chem. 2007;387:371-380.

    Not in our library10.1007/s00216-006-0720-y

  149. 149.

    Spoering AL, Gilmore MS. Quorum sensing and DNA release in bacterial biofilms. Curr Opin Microbiol. 2006;9:133-137.

    Not in our library10.1016/j.mib.2006.02.004

  150. 150.

    Suntharalingam P, Cvitkovitch DG. Quorum sensing in streptococcal biofilm formation. Trends Microbiol. 2005;13:3-6.

    Not in our library10.1016/j.tim.2004.11.009

  151. 151.

    Chen G, Swem LR, Swem DL, Stauff DL, O’Loughlin CT, Jeffrey PD, Bassler BL, Hughson FM. A strategy for antagonizing quorum sensing. Mol Cell. 2011;42:199-209.

    Not in our library10.1016/j.molcel.2011.04.003

  152. 152.

    Waters CM, Bassler BL. Quorum sensing: Cell-to-cell communication in bacteria. Annu Rev Cell Dev Biol. 2005;21:319-346.

    Not in our library10.1146/annurev.cellbio.21.012704.131001

  153. 153.

    Sutherland I. Biofilm exopolysaccharides: A strong and sticky framework. Microbiology. 2001;147:3-9.

    Not in our library10.1099/00221287-147-1-3

  154. 154.

    Moreau-Marquis S, Stanton BA, O’Toole GA. Pseudomonas aeruginosa biofilm formation in the cystic fibrosis airway. Pulm Pharmacol Ther. 2008;21:595-599.

    Not in our library10.1016/j.pupt.2007.12.001

  155. 155.

    Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 2008;76:4176-4182.

    Not in our library10.1128/iai.00318-08

  156. 156.

    Hell E, Giske CG, Nelson A, Römling U, Marchini G. Human cathelicidin peptide LL37 inhibits both attachment capability and biofilm formation of Staphylococcus epidermidis. Lett Appl Microbiol. 2010;50:211-215.

    Not in our library10.1111/j.1472-765x.2009.02778.x

  157. 157.

    Amer LS, Bishop BM, van Hoek ML. Antimicrobial and antibiofilm activity of cathelicidins and short, synthetic peptides against Francisella. Biochem Biophys Res Commun. 2010;396:246-251.

    Not in our library10.1016/j.bbrc.2010.04.073

  158. 158.

    Porat Y, Marynka K, Tam A, Steinberg D, Mor A. Acyl-substituted dermaseptin S4 derivatives with improved bactericidal properties, including on oral microflora. Antimicrob Agents Chemother. 2005;50:4153-4160.

    Not in our library10.1128/aac.00750-06

  159. 159.

    Laverty G, McLaughlin M, Shaw C, Gorman SP, Gilmore BF. Antimicrobial activity of short, synthetic cationic lipopeptides. Chem Biol Drug Des. 2010;75:563-569.

    Not in our library10.1111/j.1747-0285.2010.00973.x

  160. 160.

    Roveta S, Marchese A, Schito GC. Activity of daptomycin on biofilms produced on a plastic support by Staphylococcus spp. Int J Antimicrob Agents. 2008;31:321-328.

    Not in our library10.1016/j.ijantimicag.2007.11.012

  161. 161.

    H⊘iby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents. 2010;35:322-332.

    Not in our library10.1016/j.ijantimicag.2009.12.011

  162. 162.

    Yoshinari M, Kato T, Matsuzaka K, Hayakawa T, Shiba K. Prevention of biofilm formation on titanium surfaces modified with conjugated molecules comprised of antimicrobial and titanium-binding peptides. Biofouling. 2010;26:103-110.

    Not in our library10.1080/08927010903216572

  163. 163.

    Willcox MD, Hume EB, Aliwarga Y, Kumar N, Cole N. A novel cationic-peptide coating for the prevention of microbial colonization on contact lenses. J Appl Microbiol. 2008;105:1817-1825.

    Not in our library10.1111/j.1365-2672.2008.03942.x

  164. 164.

    Cole N, Hume EB, Vijay AK, Sankaridurg P, Kumar N, Willcox MD. In vivo performance of melimine as an antimicrobial coating for contact lenses in models of CLARE and CLPU. Invest Ophthalmol Vis Sci. 2010;51:390-395.

    Not in our library10.1167/iovs.09-4068

  165. 165.

    Cirioni O, Giacometti A, Ghiselli R, Kamysz W, Orlando F, Mocchegiani F, Silvestri C, Licci A, Chiodi L, Lukasiak J, Saba V, Scalise G. Citropin 1.1-treated central venous catheters improve the efficacy of hydrophobic antibiotics in the treatment of experimental staphylococcal catheter-related infection. Peptides. 2006;27:1210-1216.

    Not in our library10.1016/j.peptides.2005.10.007

  166. 166.

    Marsh PD. Dental plaque: Biological significance of a biofilm and community life-style. J Clin Periodontol. 2005;32:7-15.

    Not in our library10.1111/j.1600-051x.2005.00790.x

  167. 167.

    Rudney JD. Saliva and dental plaque. Adv Dent Res. 2000;14:29-39.

    Not in our library10.1177/08959374000140010401

  168. 168.

    Marsh PD, Bradshaw DJ. Dental plaque as a biofilm. J Ind Microbiol. 1995;15:169-175.

    Not in our library10.1007/bf01569822

  169. 169.

    Sissons CH, Anderson SA, Wong L, Coleman MJ, White DC. Microbiota of plaque microcosm biofilms: Effect of three times daily sucrose pulses in different simulated oral environments. Caries Res. 2007;41:413-422.

    Not in our library10.1159/000104801

  170. 170.

    Filoche S, Wong L, Sissons CH. Oral biofilms: Emerging concepts in microbial ecology. J Dent Res. 2010;89:8-18.

    Not in our library10.1177/0022034509351812

  171. 171.

    Leung KP, Abercrombie JJ, Campbell TM, Gilmore KD, Bell CA, Faraj JA, DeLuca PP. Antimicrobial peptides for plaque control. Adv Dent Res. 2009;21:57-62.

    Not in our library10.1177/0895937409335627

  172. 172.

    Eberhard J, Pietschmann R, Falk W, Jepsen S, Dommisch H. The immune response of oral epithelial cells induced by single-species and complex naturally formed biofilms. Oral Microbiol Immunol. 2009;24:325-330.

    Not in our library10.1111/j.1399-302x.2009.00518.x

  173. 173.

    Lobos O, Padilla A, Padilla C. In vitro antimicrobial effect of bacteriocin PsVP-10 in combination with chlorhexidine and triclosan against Streptococcus mutans and Streptococcus sobrinus strains. Arch Oral Biol. 2009;54:230-234.

    Not in our library10.1016/j.archoralbio.2008.11.007

  174. 174.

    Wakabayashi H, Yamauchi K, Kobayashi T, Yaeshima T, Iwatsuki K, Yoshie H. Inhibitory effects of lactoferrin on growth and biofilm formation of Porphyromonas gingivalis and Prevotella intermedia. Antimicrob Agents Chemother. 2009;53:3308-3316.

    Not in our library10.1128/aac.01688-08

  175. 175.

    Arslan SY, Leung KP, Wu CD. The effect of lactoferrin on oral bacterial attachment. Oral Microbiol Immunol. 2009;24:411-416.

    Not in our library10.1111/j.1399-302x.2009.00537.x

  176. 176.

    Wakabayashi H, Kondo I, Kobayashi T, Yamauchi K, Toida T, Iwatsuki K, Yoshie H. Periodontitis, periodontopathic bacteria and lactoferrin. Biometals. 2010;23:419-424.

    Not in our library10.1007/s10534-010-9304-6

  177. 177.

    Darouiche RO, Mansouri MD, Gawande PV, Madhyastha S. Antimicrobial and antibiofilm efficacy of triclosan and DispersinB combination. J Antimicrob Chemother. 2009;64:88-93.

    Not in our library10.1093/jac/dkp158

  178. 178.

    Kaplan JB. Therapeutic potential of biofilm-dispersing enzymes. Int J Artif Organs. 2009;32:545-554.

    Not in our library10.1177/039139880903200903

  179. 179.

    Izano EA, Amarante MA, Kher WB, Kaplan JB. Differential roles of poly-N-acetylglucosamine surface polysaccharide and extracellular DNA in Staphylococcus aureus and Staphylococcus epidermidis biofilms. Appl Environ Microbiol. 2008;74:470-476.

    Not in our library10.1128/aem.02073-07

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