Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
FEBS J. 2020 Oct;287(20):4341-4353. doi: 10.1111/febs.15370. Epub 2020 Jun 8.
Drug-resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less subject to existing resistance mechanisms, history shows that this strategy by itself is unlikely to solve the problem of drug resistance. Here, we discuss inhibiting evolution as a strategy that, in combination with antibiotics, may resolve the problem. Although mutagenesis is the main driver of drug resistance development, attacking the drivers of genetic diversification in pathogens has not been well explored. Bacteria possess active mechanisms that increase the rate of mutagenesis, especially at times of stress, such as during replication within eukaryotic host cells, or exposure to antibiotics. We highlight how the existence of these promutagenic proteins (evolvability factors) presents an opportunity that can be capitalized upon for the effective inhibition of drug resistance development. To help move this idea from concept to execution, we first describe a set of criteria that an 'optimal' evolvability factor would likely have to meet to be a viable therapeutic target. We then discuss the intricacies of some of the known mutagenic mechanisms and evaluate their potential as drug targets to inhibit evolution. In principle, and as suggested by recent studies, we argue that the inhibition of these and other evolvability factors should reduce resistance development. Finally, we discuss the challenges of transitioning anti-evolution drugs from the laboratory to the clinic.
耐药细菌感染已导致全球性健康危机。尽管人们投入大量精力开发不易受现有耐药机制影响的新型抗生素或变体，但历史表明，仅靠这种策略不太可能解决耐药问题。在这里，我们讨论了将抑制进化作为一种策略，该策略与抗生素联合使用，可能有助于解决耐药问题。尽管突变是耐药性发展的主要驱动因素，但攻击病原体遗传多样化的驱动因素尚未得到充分探索。细菌具有提高突变率的主动机制，尤其是在真核宿主细胞内复制或暴露于抗生素时。我们强调了这些促突变蛋白（可进化性因素）的存在如何为有效抑制耐药性发展提供了一个可以利用的机会。为了帮助将这一想法从概念转化为实践，我们首先描述了一套标准，即一个“理想的”可进化性因素要成为可行的治疗靶点，可能需要满足哪些条件。然后，我们讨论了一些已知的突变机制的复杂性，并评估了它们作为抑制进化的药物靶点的潜力。原则上，正如最近的研究表明的那样，我们认为抑制这些和其他可进化性因素应能减少耐药性的发展。最后，我们讨论了将抗进化药物从实验室过渡到临床的挑战。
