The Unique Challenge: Why Microbes Struggle to Develop Resistance to Antimicrobial Peptides
DOI:
https://doi.org/10.33687/ricosbiol.03.010.85Keywords:
antimicrobial peptides, antimicrobial resistance, drug development, membrane disruption, fitness cost, innate immunity, host defence peptides, evolutionary trade-offsAbstract
The escalating crisis of antimicrobial resistance (AMR) threatens to unravel a century of medical progress. Conventional antibiotics, with their specific, single-target mechanisms, are increasingly rendered ineffective, necessitating the urgent development of novel therapeutic strategies. Antimicrobial Peptides (AMPs), fundamental components of the innate immune system across all kingdoms of life, have emerged as promising candidates. A pivotal advantage of AMPs over traditional antibiotics is the perceived difficulty for microbes to develop robust resistance against them. This review delves into the mechanistic underpinnings of this phenomenon, exploring the unique mode of action of AMPs, the fitness costs associated with resistance mechanisms, and the evolutionary trade-offs that constrain microbial adaptation. While acknowledging that resistance is not impossible, we argue that the inherent properties of AMPs present a significantly higher and more complex barrier for resistance development compared to conventional drugs.
Downloads
References
Andersson, D. I., and Hughes, D. (2010). Antibiotic resistance and its cost: is it possible to reverse resistance? Nature Reviews Microbiology, 8(4), 260–271. https://doi.org/10.1038/nrmicro2319
Batoni, G., Maisetta, G., and Esin, S. (2016). Antimicrobial peptides and their interaction with biofilms of medically relevant bacteria. *Biochimica et Biophysica Acta (BBA) - Biomembranes, 1858*(5), 1044–1060. https://doi.org/10.1016/j.bbamem.2015.10.013
Blair, J. M. A., Webber, M. A., Baylay, A. J., Ogbolu, D. O., and Piddock, L. J. V. (2015). Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology, 13(1), 42–51. https://doi.org/10.1038/nrmicro3380
Brogden, K. A. (2005). Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nature Reviews Microbiology, 3(3), 238–250. https://doi.org/10.1038/nrmicro1098
Ernst, C. M., and Peschel, A. (2011). MprF-mediated daptomycin resistance. International Journal of Medical Microbiology, 301(8), 642–645. https://doi.org/10.1016/j.ijmm.2011.08.015
Fox, J. L. (2013). Antimicrobial peptides stage a comeback. Nature Biotechnology, 31(5), 379–382. https://doi.org/10.1038/nbt.2572
Guo, L., Lim, K. B., Gunn, J. S., Bainbridge, B., Darveau, R. P., Hackett, M., and Miller, S. I. (1998). Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ. Science, 276(5310), 250–253. https://doi.org/10.1126/science.276.5310.250
Gupta, S., Kapoor, P., Chaudhary, K., Gautam, A., Kumar, R., and Raghava, G. P. S. (2017). Peptide toxicity prediction. In Computational Peptidology (pp. 143-157). Springer. https://doi.org/10.1007/978-1-4939-6798-8_8
Hale, J. D., and Hancock, R. E. (2007). Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. *Expert Review of Anti-infective Therapy, 5*(6), 951–959. https://doi.org/10.1586/14787210.5.6.951
Hancock, R. E. W., and Sahl, H.-G. (2006). Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology, 24(12), 1551–1557. https://doi.org/10.1038/nbt1267
Koprivnjak, T., and Peschel, A. (2011). Bacterial resistance mechanisms against host defense peptides. Cellular and Molecular Life Sciences, 68(13), 2243–2254. https://doi.org/10.1007/s00018-011-0716-4
Lei, J., Sun, L., Huang, S., Zhu, C., Li, P., He, J., Mackey, V., Coy, D. H., and He, Q. (2019). The antimicrobial peptides and their potential clinical applications. American Journal of Translational Research, 11(7), 3919–3931.
Melo, M. N., Ferre, R., and Castanho, M. A. R. B. (2009). Antimicrobial peptides: linking partition, activity and high membrane-bound concentrations. Nature Reviews Microbiology, 7(3), 245–250. https://doi.org/10.1038/nrmicro2095
Nizet, V. (2006). Antimicrobial peptide resistance mechanisms of human bacterial pathogens. Current Issues in Molecular Biology, 8(1), 11–26.
Peschel, A., Jack, R. W., Otto, M., Collins, L. V., Staubitz, P., Nicholson, G., Kalbacher, H., Nieuwenhuizen, W. F., Jung, G., Tarkowski, A., van Kessel, K. P., and van Strijp, J. A. (2001). Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with l-lysine. The Journal of Experimental Medicine, 193(9), 1067–1076. https://doi.org/10.1084/jem.193.9.1067
Piddock, L. J. V. (2006). Multidrug-resistance efflux pumps? not just for resistance. Nature Reviews Microbiology, 4(8), 629–636. https://doi.org/10.1038/nrmicro1464
Schmidtchen, A., Frick, I. M., Andersson, E., Tapper, H., and Björck, L. (2002). Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Molecular Microbiology, 46(1), 157–168. https://doi.org/10.1046/j.1365-2958.2002.03146.x
Shafer, W. M., Qu, X., Waring, A. J., and Lehrer, R. I. (1998). Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proceedings of the National Academy of Sciences, 95(4), 1829–1833. https://doi.org/10.1073/pnas.95.4.1829
World Health Organization. (2024, April 23). Antimicrobial resistance. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance
Zasloff, M. (2002). Antimicrobial peptides of multicellular organisms. Nature, 415(6870), 389–395. https://doi.org/10.1038/415389a
Published
Data Availability Statement
Copyright: Copyrights retained to the Authors., Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/ by/4.0/),which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Issue
Section
Categories
License
Copyright (c) 2025 Hussein Abouelhag
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/ by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
