Antimicrobial peptides with limited resistance

Antimicrobial peptides with limited resistance

Antibiotic resistance is an ever-growing problem in health care, based on three interconnected facts: (1) multidrug resistant infections with no effective treatment are spreading in the clinic; (2) resistance to newly developed antibiotics evolves very quickly, and (3) the huge costs but the short life-span of a new antibacterial agent discourages antibiotic development.
Therefore, scientists are seeking alternative solutions, which has generated a growing interest in antimicrobial peptides (AMPs) present in all kingdoms of life for billions of years. These agents may offer a solution against multidrug resistant bacteria. However, comprehensive studies on the resistance potential of bacteria against AMPs, a clue to the development of effective antimicrobials, are still missing. Revealing this key characteristic of a drug candidate at an early stage of development allows to select for less resistance prone molecules.

Unfortunately, predicting resistance is challenging, as resistance evolution is driven by complex processes in nature. Mutations may evolve in bacteria and induce various effects, including the modification of the drug’s target, making the agent ineffective. These novel traits are passed on, and thus can spread in the population. Also, bacteria may obtain genetic material from other bacteria, often leading to multidrug-resistance, a problem that should definitely be considered, as multidrug-resistant bacteria may be less susceptible (cross-resistant) to certain AMPs. 

Interestingly, bacteria are reported to be less prone to developing resistance against AMPs compared to antibiotics, however this claim is disputable. Most published studies on resistance evolution against AMPs focused on individual peptides only and did not consider the complexity of resistance spreading. 

Therefore, we investigated microbial resistance potential of Escherichia coli against a wide range of AMPs with different structures and modes of action, using antibiotics for comparison. Our first important finding is that the adaptation ability against AMPs is not “black or white”, as parallel evolving populations were found to develop AMP resistance with varying success, compared to the significant resistance evolution against antibiotics.  

Most remarkably, we found that no significant resistance in E.coli evolves against some AMPs. Importantly, no cross-resistance was detected towards these peptides. Finally, neither artificial gene amplification, nor horizontal gene transfer from soil bacteria was found to provide resistance against these AMPs. This research, along with our previous studies, indicates that some AMPs could be promising drug candidates. For years, researchers in the Pál lab have been studying resistance against AMPs from various aspects. In 2018, Lázár et al. reported that antibiotic resistant E. coli strains are sensitive to certain AMPs 1. Earlier this year Kintses et al. have revealed that the horizontal transfer of AMP resistance genes from the human gut microbiome is constrained by phylogenetic barriers 2. Our three complementary research works provide a complex investigation into AMP resistance and raise new, exciting questions. Are there any differences between the adaptation ability of bacterial species to AMPs? How does resistance affect virulence and antibiotic sensitivity of bacteria? Future research may provide answers to these questions, contributing to a better understanding of resistance evolution against AMPs. 

Csaba Pál group

1. Lázár, V. et al. Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides. Nat. Microbiol. 3, 718–731 (2018).
2. Kintses, B. et al. Phylogenetic barriers to horizontal transfer of antimicrobial peptide resistance genes in the human gut microbiota. Nat. Microbiol. 4, 447–458 (2019).

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