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.
Department of Microbiology, University of Washington, Seattle, WA, USA.
Mol Cell. 2019 Jan 3;73(1):157-165.e5. doi: 10.1016/j.molcel.2018.10.015. Epub 2018 Nov 15.
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.
人们通常致力于开发新型抗生素来对抗抗菌药物耐药性（AMR）。然而，历史表明，无论新药物的性质或效力如何，耐药性都会产生。在这里，我们提出并提供了证据，证明了一种解决这个问题的替代策略：抑制进化。我们确定 DNA 易位酶 Mfd 是一种“可进化性因子”，可促进突变，并有助于对抗所有测试的抗生素在高度不同的细菌物种中快速产生耐药性。重要的是，至少在抗甲氧苄啶耐药性的进化过程中，没有 Mfd 就不会产生加速 AMR 发展的高突变体等位基因。我们还表明，Mfd 在 AMR 发展中的作用取决于其与 RNA 聚合酶亚基 RpoB 和核苷酸切除修复蛋白 UvrA 的相互作用。我们的研究结果表明，可以通过失活可进化性因子（可能使用“反进化”药物）来抑制 AMR 发展-特别是 Mfd-为对抗 AMR 危机提供了一条尚未开发的途径。
