Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance

Réka Spohn,Mónika Számel,Zoltán Bódi,Balázs Papp,Ana Martins,Csaba Pál,Orsolya Méhi,Bálint Csörgő,Bálint Kintses,Imre Földesi,Anikó Faragó,László Bodai,Ádám Györkei,Gergely Maróti,Gábor Grézal,Viktória Lázár,Fanni Vidovics,Lejla Daruka,Bernadett Pap,Pramod Kumar Jangir ,Roland Wirth,D Kata

doi:10.1038/s41467-019-12364-6

Abstract

Antimicrobial peptides (AMPs) are promising antimicrobials, however, the potential of bacterial resistance is a major concern. Here we systematically study the evolution of resistance to 14 chemically diverse AMPs and 12 antibiotics in Escherichia coli. Our work indicates that evolution of resistance against certain AMPs, such as tachyplesin II and cecropin P1, is limited. Resistance level provided by point mutations and gene amplification is very low and antibiotic-resistant bacteria display no cross-resistance to these AMPs. Moreover, genomic fragments derived from a wide range of soil bacteria confer no detectable resistance against these AMPs when introduced into native host bacteria on plasmids. We have found that simple physicochemical features dictate bacterial propensity to evolve resistance against AMPs. Our work could serve as a promising source for the development of new AMP-based therapeutics less prone to resistance, a feature necessary to avoid any possible interference with our innate immune system.

Highlights

Antimicrobial peptides (AMPs) are promising antimicrobials, the potential of bacterial resistance is a major concern
We have focused on four AMP candidates found to be less prone to resistance induced by genomic mutations (R8, IND, tachyplesin II (TPII) and cecropin P1 (CP1), Fig. 1a), and four, clinically relevant small-molecule antibiotics with diverse modes of action (TRM, TOB, CHL, and CPR)
We investigated these issues with a range of clinically relevant antibiotics and functionally/chemically diverse AMPs

Summary

Introduction

Antimicrobial peptides (AMPs) are promising antimicrobials, the potential of bacterial resistance is a major concern. AMPs can interfere with central cellular processes, such as DNA and protein syntheses, protein folding, and cell wall synthesis[5,6] Given their broad spectrum of activity, much effort has been made to find potential novel antibacterial drug candidates among AMPs, skeptics have raised issues concerning low peptide stability, costly production, and pleiotropic biological effects[7,8]. There are reasonable concerns that the therapeutic use of certain AMPs could drive a rapid evolution of resistance to host-defense peptides with immunerelated functions in the human body[15,16] This is a pressing issue, as several synthetic AMPs are currently tested in clinical trials (the majority of them are proposed for topical use)[2,3]. It is of central importance to compare the rate of resistance evolution against AMPs and clinically employed antibiotics

Methods

Results

Conclusion