Antimicrobials, stress and mutagenesis.

Alexandro Rodríguez-Rojas,Olga Makarova,Jens Rolff,Michael Zasloff

doi:10.1371/journal.ppat.1004445

Alexandro Rodríguez-Rojas, Olga Makarova + Show 2 more

Open Access

https://doi.org/10.1371/journal.ppat.1004445

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Journal: PLoS pathogens	Publication Date: Oct 9, 2014
Citations: 109	License type: CC BY 4.0

Affiliation: Freie Universität Berlin

Abstract

Cationic antimicrobial peptides are ancient and ubiquitous immune effectors that multicellular organisms use to kill and police microbes whereas antibiotics are mostly employed by microorganisms. As antimicrobial peptides (AMPs) mostly target the cell wall, a microbial ‘Achilles heel’, it has been proposed that bacterial resistance evolution is very unlikely and hence AMPs are ancient ‘weapons’ of multicellular organisms. Here we provide a new hypothesis to explain the widespread distribution of AMPs amongst multicellular organism. Studying five antimicrobial peptides from vertebrates and insects, we show, using a classic Luria-Delbrück fluctuation assay, that cationic antimicrobial peptides (AMPs) do not increase bacterial mutation rates. Moreover, using rtPCR and disc diffusion assays we find that AMPs do not elicit SOS or rpoS bacterial stress pathways. This is in contrast to the main classes of antibiotics that elevate mutagenesis via eliciting the SOS and rpoS pathways. The notion of the ‘Achilles heel’ has been challenged by experimental selection for AMP-resistance, but our findings offer a new perspective on the evolutionary success of AMPs. Employing AMPs seems advantageous for multicellular organisms, as it does not fuel the adaptation of bacteria to their immune defenses. This has important consequences for our understanding of host-microbe interactions, the evolution of innate immune defenses, and also sheds new light on antimicrobial resistance evolution and the use of AMPs as drugs.

Highlights

Ever since the advent of antibiotics, bacterial resistance has evolved and spread very rapidly [1] and recently has been shown to be ancient [2]
Mutation rates of E. coli treated with antimicrobial peptides and antibiotics
Cationic antimicrobial peptides are ancient and ubiquitous immune effectors that multicellular organisms use to kill and police microbes, whilst antibiotics are mostly employed by microorganisms

Summary

Introduction

Ever since the advent of antibiotics, bacterial resistance has evolved and spread very rapidly [1] and recently has been shown to be ancient [2] This led to the suggestion to use cationic antimicrobial peptides (AMPs) as alternatives, as these have been successfully used by multicellular organisms over millions of years [3]. Antibiotics mostly interfere with replication, transcription and protein synthesis, in contrast cationic antimicrobial peptides of multicellular organisms mostly target the cell wall [12] As such there is little potential of eliciting the SOS or rpoS stress pathways and to elevate bacterial mutation rates, a notion that we test here. This addresses the novel hypothesis that the use of antimicrobial peptides in multicellular organisms as a main effector against pathogens has been selected for because of the differences in mutagenesis between AMPs and antibiotics

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Conclusion