Inhibiting the Evolution of Antibiotic Resistance

Mark N Ragheb,Maureen K Thomason,Chris Hsu,Patrick Nugent,John Gage,Ariana N Samadpour,Ankunda Kariisa,Christopher N Merrikh,Samuel I Miller,David R Sherman,Houra Merrikh

doi:10.1016/j.molcel.2018.10.015

Abstract

SummaryEfforts to battle antimicrobial resistance (AMR) are generally focused on developing novel antibiotics. However, history shows that resistance arises regardless of the nature or potency of new drugs. Here, we propose and provide evidence for an alternate strategy to resolve this problem: inhibiting evolution. We determined that the DNA translocase Mfd is an “evolvability factor” that promotes mutagenesis and is required for rapid resistance development to all antibiotics tested across highly divergent bacterial species. Importantly, hypermutator alleles that accelerate AMR development did not arise without Mfd, at least during evolution of trimethoprim resistance. We also show that Mfd’s role in AMR development depends on its interactions with the RNA polymerase subunit RpoB and the nucleotide excision repair protein UvrA. Our findings suggest that AMR development can be inhibited through inactivation of evolvability factors (potentially with “anti-evolution” drugs)—in particular, Mfd—providing an unexplored route toward battling the AMR crisis.

Highlights

The battle between antimicrobial-resistant pathogens and antibiotic therapy is an evolutionary arms race—one that we are currently losing
Most efforts to resolve antimicrobial resistance (AMR) are geared toward the development of novel antibiotics, yet resistance has arisen to every antibiotic used in the clinic
Divergent Bacterial Species The role of Mfd in DNA repair has remained controversial: cells lacking Mfd are not sensitive to DNA-damaging agents and previous work hints at a mutagenic role transcription elongation

Summary

Introduction

The battle between antimicrobial-resistant pathogens and antibiotic therapy is an evolutionary arms race—one that we are currently losing. Antimicrobial resistance (AMR)related deaths have reached alarming rates throughout the world. Given the alarming global burden of TB drug resistance in addition to the rise of chromosomally acquired AMR in many other pathogens, reducing the mutational capacity of organisms could significantly inhibit their ability to develop AMR. This approach requires the identification and subsequent inhibition of active factors that increase mutation rates. We term these proteins ‘‘evolvability factors’’ given that they can promote evolution by increasing mutation rates (either directly or indirectly)

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