Molecular Medicine Israel

Inhibiting the Evolution of Antibiotic Resistance

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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