Format

Send to

Choose Destination
Mol Cell. 2018 Nov 8. pii: S1097-2765(18)30847-5. doi: 10.1016/j.molcel.2018.10.015. [Epub ahead of print]

Inhibiting the Evolution of Antibiotic Resistance.

Author information

1
Department of Microbiology, University of Washington, Seattle, WA, USA; Molecular and Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
2
Department of Microbiology, University of Washington, Seattle, WA, USA.
3
Department of Microbiology, University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
4
Center for Infectious Disease Research, Seattle, WA, USA; Interdiscipinary Program of Pathobiology, Department of Global Health, University of Washington, Seattle, WA, USA.
5
Department of Microbiology, University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: merrikh@uw.edu.

Abstract

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.

KEYWORDS:

Mfd; Mycobacteria; anti-evolution; antibiotic resistance; antimicrobial resistance; evolution; hypermutator; transcription-coupled repair

PMID:
30449724
DOI:
10.1016/j.molcel.2018.10.015
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center