Mode-of-Action of Antimicrobial Peptides: Membrane Disruption Vs. Intracellular Mechanisms

Overview

Journal Front Med Technol

Specialty Biomedical Engineering

Date 2022 Jan 20

PMID 35047892

Authors

Aurelie H Benfield

Sonia Troeira Henriques

Affiliations

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Abstract

Antimicrobial peptides are an attractive alternative to traditional antibiotics, due to their physicochemical properties, activity toward a broad spectrum of bacteria, and mode-of-actions distinct from those used by current antibiotics. In general, antimicrobial peptides kill bacteria by either disrupting their membrane, or by entering inside bacterial cells to interact with intracellular components. Characterization of their mode-of-action is essential to improve their activity, avoid resistance in bacterial pathogens, and accelerate their use as therapeutics. Here we review experimental biophysical tools that can be employed with model membranes and bacterial cells to characterize the mode-of-action of antimicrobial peptides.

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References

Cardoso M, Meneguetti B, Costa B, Buccini D, Oshiro K, Preza S . Non-Lytic Antibacterial Peptides That Translocate Through Bacterial Membranes to Act on Intracellular Targets. Int J Mol Sci. 2019; 20(19). PMC: 6801614. DOI: 10.3390/ijms20194877. View

Lee T, Hofferek V, Separovic F, Reid G, Aguilar M . The role of bacterial lipid diversity and membrane properties in modulating antimicrobial peptide activity and drug resistance. Curr Opin Chem Biol. 2019; 52:85-92. DOI: 10.1016/j.cbpa.2019.05.025. View

Benfield A, Defaus S, Lawrence N, Chaousis S, Condon N, Cheneval O . Cyclic gomesin, a stable redesigned spider peptide able to enter cancer cells. Biochim Biophys Acta Biomembr. 2020; 1863(1):183480. DOI: 10.1016/j.bbamem.2020.183480. View

Pirtskhalava M, Amstrong A, Grigolava M, Chubinidze M, Alimbarashvili E, Vishnepolsky B . DBAASP v3: database of antimicrobial/cytotoxic activity and structure of peptides as a resource for development of new therapeutics. Nucleic Acids Res. 2020; 49(D1):D288-D297. PMC: 7778994. DOI: 10.1093/nar/gkaa991. View

Farkas A, Maroti G, Durgo H, Gyorgypal Z, Lima R, Medzihradszky K . Medicago truncatula symbiotic peptide NCR247 contributes to bacteroid differentiation through multiple mechanisms. Proc Natl Acad Sci U S A. 2014; 111(14):5183-8. PMC: 3986156. DOI: 10.1073/pnas.1404169111. View

Stiefel P, Schmidt-Emrich S, Maniura-Weber K, Ren Q . Critical aspects of using bacterial cell viability assays with the fluorophores SYTO9 and propidium iodide. BMC Microbiol. 2015; 15:36. PMC: 4337318. DOI: 10.1186/s12866-015-0376-x. View

Weinstein J, Klausner R, Innerarity T, Ralston E, Blumenthal R . Phase transition release, a new approach to the interaction of proteins with lipid vesicles. Application to lipoproteins. Biochim Biophys Acta. 1981; 647(2):270-84. DOI: 10.1016/0005-2736(81)90255-8. View

Hsu C, Chen C, Jou M, Lee A, Lin Y, Yu Y . 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(13):4053-64. PMC: 1179735. DOI: 10.1093/nar/gki725. View

Lei J, Sun L, Huang S, Zhu C, Li P, He J . The antimicrobial peptides and their potential clinical applications. Am J Transl Res. 2019; 11(7):3919-3931. PMC: 6684887. View

10.

Philippe G, Gaspar D, Sheng C, Huang Y, Benfield A, Condon N . Cell Membrane Composition Drives Selectivity and Toxicity of Designed Cyclic Helix-Loop-Helix Peptides with Cell Penetrating and Tumor Suppressor Properties. ACS Chem Biol. 2019; 14(9):2071-2087. DOI: 10.1021/acschembio.9b00593. View

11.

Jiang X, Yang K, Yuan B, Gong B, Wan L, Patil N . Simulations of octapeptin-outer membrane interactions reveal conformational flexibility is linked to antimicrobial potency. J Biol Chem. 2020; 295(47):15902-15912. PMC: 7681018. DOI: 10.1074/jbc.RA120.014856. View

12.

Stewart J . Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal Biochem. 1980; 104(1):10-4. DOI: 10.1016/0003-2697(80)90269-9. View

13.

Tugyi R, Uray K, Ivan D, Fellinger E, Perkins A, Hudecz F . Partial D-amino acid substitution: Improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proc Natl Acad Sci U S A. 2005; 102(2):413-8. PMC: 544305. DOI: 10.1073/pnas.0407677102. View

14.

Cardoso M, Orozco R, Rezende S, Rodrigues G, Oshiro K, Candido E . Computer-Aided Design of Antimicrobial Peptides: Are We Generating Effective Drug Candidates?. Front Microbiol. 2020; 10:3097. PMC: 6987251. DOI: 10.3389/fmicb.2019.03097. View

15.

Ghosh C, Sarkar P, Issa R, Haldar J . Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance. Trends Microbiol. 2019; 27(4):323-338. DOI: 10.1016/j.tim.2018.12.010. View

16.

Hancock R, Farmer S . Mechanism of uptake of deglucoteicoplanin amide derivatives across outer membranes of Escherichia coli and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1993; 37(3):453-6. PMC: 187692. DOI: 10.1128/AAC.37.3.453. View

17.

Kaplan C, Sim J, Shah K, Kolesnikova-Kaplan A, Shi W, Eckert R . Selective membrane disruption: mode of action of C16G2, a specifically targeted antimicrobial peptide. Antimicrob Agents Chemother. 2011; 55(7):3446-52. PMC: 3122425. DOI: 10.1128/AAC.00342-11. View

18.

Roth B, Poot M, YUE S, Millard P . Bacterial viability and antibiotic susceptibility testing with SYTOX green nucleic acid stain. Appl Environ Microbiol. 1997; 63(6):2421-31. PMC: 168536. DOI: 10.1128/aem.63.6.2421-2431.1997. View

19.

Limoli D, Rockel A, Host K, Jha A, Kopp B, Hollis T . Cationic antimicrobial peptides promote microbial mutagenesis and pathoadaptation in chronic infections. PLoS Pathog. 2014; 10(4):e1004083. PMC: 3999168. DOI: 10.1371/journal.ppat.1004083. View

20.

Mishra B, Reiling S, Zarena D, Wang G . Host defense antimicrobial peptides as antibiotics: design and application strategies. Curr Opin Chem Biol. 2017; 38:87-96. PMC: 5494204. DOI: 10.1016/j.cbpa.2017.03.014. View