Inhibiting the Evolution of Antibiotic Resistance
Mark N. Ragheb 1 2 Maureen K. Thomason 1 Chris Hsu 1 Patrick Nugent 1 John Gage 1 Ariana N. Samadpour 1 Ankunda Kariisa 1Christopher N. Merrikh 1 Samuel I. Miller 1 3 David R. Sherman 4 5 Houra Merrikh 1 3 6
1 Department of Microbiology, University of Washington, Seattle, WA, USA
2 Molecular and Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA, USA
3 Department of Genome Sciences, University of Washington, Seattle, WA, USA
4 Center for Infectious Disease Research, Seattle, WA, USA
5 Interdiscipinary Program of Pathobiology, Department of Global Health, University of Washington, Seattle, WA, USA
Received 15 June 2018, Revised 17 August 2018, Accepted 9 October 2018, Available online 15 November 2018.
Published: November 15, 2018
https://doi.org/10.1016/j.molcel.2018.10.015 Get rights and content
Under a Creative Commons license open access
Highlights
• The bacterial transcription-coupled repair (TCR) factor Mfd promotes mutagenesis
• Mfd-driven mutagenesis accelerates the evolution of antimicrobial resistance (AMR)
• The rapid evolution of AMR requires Mfd’s interaction with RpoB and UvrA
• Mfd may be an ideal target for “anti-evolution” drugs that inhibit AMR development
Summary
Efforts 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.
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