Mechanisms of Antimicrobial Peptide Action and Resistance

Yeaman, Michael R.; Yount, Nannette Y.

doi:10.1124/pr.55.1.2

Cited by 2,616 publications

(2,617 citation statements)

References 157 publications

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“…25,[32][33][34][35][36][37]. Therefore, synergistic bactericidal activity could result from the peptides having greater access to the cell membrane thanks to the cell wall-degrading abilities of lysostaphin.…”

Section: Discussionmentioning

confidence: 99%

“…However, therapies that contain multiple antimicrobial agents can reduce the opportunity for resistance to be selected and various lysostaphin-containing combination treatments have been investigated, including lysostaphin with: i) various antibacterial drugs used clinically [7,8,13,[15][16][17][18][19][20]; ii) tea tree oil [8]; iii) lysozyme [21]; iv) the phage lytic enzyme LysK [22]; and v) certain conventional antimicrobial peptides (AMPs) [10,15,19,23]. The incorporation of an AMP into a combination therapy further reduces the opportunity for bacterial resistance, as these compounds typically disrupt the bacterial cell membrane and resistance to AMPs is reported only rarely [24][25][26][27]. Moreover, certain lysostaphin/AMP combinations are synergistically antibacterial, which has clinical relevance as the doses of each compound can be reduced [10,15].…”

Section: Introductionmentioning

confidence: 99%

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Bactericidal synergy of lysostaphin in combination with antimicrobial peptides

Desbois

Coote

2011

Eur J Clin Microbiol Infect Dis

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Drug-resistant staphylococci are a serious problem that urgently requires the discovery of new therapeutic agents. There has been resurgence in interest for using lysostaphin (a specific anti-staphylococcal enzyme) as a treatment for infections caused by these important pathogens. However, bacterial resistance to lysostaphin is a problem but the use of a combination treatment may surmount this issue. In this present study, using viable counts from suspension incubations, lysostaphin is shown to be synergistically bactericidal in combination with various conventional antimicrobial peptides, the antimicrobial protein bovine lactoferrin, a lantibiotic (nisin), and certain lipopeptides used clinically (colistin, daptomycin and polymyxin B). Combinations that act in synergy are of clinical importance as these reduce the doses of the compounds needed for effective treatments and, most importantly, decrease the chances of resistance being selected. The use of lysostaphin in combination with a peptide may represent a new avenue to tackling drug-resistant staphylococci.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bactericidal synergy of lysostaphin in combination with antimicrobial peptides

Desbois

Coote

2011

Eur J Clin Microbiol Infect Dis

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“…Prokaryotic membranes have a high negative net charge and are predominantly composed of phosphatidylglycerol (PG), cardiolipin (CL), or phosphatidylserine (PS). In contrast, mammalian membranes are enriched in the zwitterionic phospholipids (neutral net charge) phosphatidylethanolamine (PE), phosphatidylcholine (PC) or sphingomyelin (SM) (Yeaman and Yount, 2003;Giuliani et al, 2007). Moreover, the mammalian cell membrane contains cholesterol, while the prokaryote membrane does not (Tytler et al, 1995).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…It has been reported that cholesterol can dramatically reduce the activity of AMPs by stabilizing the lipid bilayer or by directly interacting and neutralizing AMPs (Matsuzaki, 1999). Despite of the different composition, the difference on membrane asymmetry and transmembrane potential (∆ψ) also provide alternatives for AMPs (Yeaman and Yount, 2003).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Initially, driven by electrostatic forces, AMPs diffuse toward the cell membrane even from a relatively long distance (Mavri and Vogel, 1996). It is hypothesized that the negative charge on the outer bacterial envelope (the phosphate groups from Gram-negative bacteria, and the lipoteichoic acids from Gram-positive bacteria) (Yeaman and Yount, 2003;Jenssen et al, 2006) and the strong electrochemical gradient (∆ψ) of the bacterial cytoplasmic membrane both contribute to the attraction of cationic AMPs (Yeaman and Yount, 2003). For Gram-negative bacteria, a mechanism termed "self-promoted uptake" has been suggested by Hancock (Hancock, 1997).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Alpha-helical cationic antimicrobial peptides: relationships of structure and function

2010

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Antimicrobial peptides (AMPs), with their extraordinary properties, such as broad-spectrum activity, rapid action and difficult development of resistance, have become promising molecules as new antibiotics. Despite their various mechanisms of action, the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action. Moreover, it is generally accepted that the membrane is the primary target of most AMPs, and the interaction between AMPs and eukaryotic cell membranes (causing toxicity to host cells) limits their clinical application. Therefore, researchers are engaged in reforming or de novo designing AMPs as a 'singleedged sword' that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells. To improve the antimicrobial activity of AMPs, the relationship between the structure and function of AMPs has been rigorously pursued. In this review, we focus on the current knowledge of α-helical cationic antimicrobial peptides, one of the most common types of AMPs in nature.

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Antimicrobial Peptides

Mor

2001

Kirk-Othmer Encyclopedia of Chemical Technology

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Antimicrobial peptides (AMPs), important effector molecules of the innate immune system, also provide templates for designing novel antibiotics. Protegrin, an especially potent AMP found in porcine leukocytes, was recently shown to form octameric transmembrane pores. We have employed a combination of experiments and models spanning length scales from the atomistic to the cellular level in order to elucidate the microbicidal mechanism of protegrin. Comparison of the modeling and experimental data suggests that approximately 10-100 protegrin pores are necessary to explain the observed rates of potassium leakage and Escherichia coli death in exponential-phase bacteria. The kinetics of viability loss suggest that bacterial death results largely from uncontrolled ion exchange processes and decay of transmembrane potential. However, ion exchange processes alone cannot account for the experimentally observed cell swelling and osmotic lysis-a redundant ''overkill'' mechanism most likely to occur in locales with high protegrin concentrations. Although our study is limited to protegrin and E. coli, the timeline of events described herein is likely shared by other AMPs that act primarily by permeabilizing microbial membranes. This work provides many of the missing links in describing antimicrobial action, as well as providing a quantitative connection between several previous experimental and simulation studies of protegrin.

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Mechanisms of Antimicrobial Peptide Action and Resistance

Cited by 2,616 publications

References 157 publications

Bactericidal synergy of lysostaphin in combination with antimicrobial peptides

Bactericidal synergy of lysostaphin in combination with antimicrobial peptides

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

Antimicrobial Peptides

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