Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, USA.
Microbiologyopen. 2022 Apr;11(2):e1273. doi: 10.1002/mbo3.1273.
The human microbiota harbors diverse bacterial and bacteriophage (phage) communities. Bacteria evolve to overcome phage infection, thereby driving phage evolution to counter bacterial resistance. Understanding how phages select for genetic alterations in medically relevant bacteria is important as phages become established biologics for the treatment of multidrug-resistant (MDR) bacterial infections. Before phages can be widely used as standalone or combination antibacterial therapies, we must obtain a deep understanding of the molecular mechanisms of phage infection and how host bacteria alter their genomes to become resistant. We performed coevolution experiments using a single Enterococcus faecalis strain and two distantly related phages to determine how phage pressure impacts the evolution of the E. faecalis genome. Whole-genome sequencing of E. faecalis following continuous exposure to these two phages revealed mutations previously demonstrated to be essential for phage infection. We also identified mutations in genes previously unreported to be associated with phage infection in E. faecalis. Intriguingly, there was only one shared mutation in the E. faecalis genome that was selected by both phages tested, demonstrating that infection by two genetically distinct phages selects for diverse variants. This knowledge serves as the basis for the continued study of E. faecalis genome evolution during phage infection and can be used to inform the design of future therapeutics, such as phage cocktails, intended to target MDR E. faecalis.
人类微生物群栖息着多样化的细菌和噬菌体（噬菌体）群落。细菌进化以克服噬菌体感染，从而推动噬菌体进化以对抗细菌的耐药性。了解噬菌体如何选择对医学相关细菌的遗传改变非常重要，因为噬菌体正在成为治疗多药耐药（MDR）细菌感染的有前途的生物疗法。在噬菌体可以广泛用作独立或联合抗菌疗法之前，我们必须深入了解噬菌体感染的分子机制以及宿主细菌如何改变其基因组以产生耐药性。我们使用单个粪肠球菌菌株和两种亲缘关系较远的噬菌体进行共进化实验，以确定噬菌体压力如何影响粪肠球菌基因组的进化。对连续暴露于这两种噬菌体的粪肠球菌进行全基因组测序，揭示了先前证明对噬菌体感染至关重要的突变。我们还鉴定了先前未报道与粪肠球菌噬菌体感染相关的基因中的突变。有趣的是，两种测试噬菌体选择的粪肠球菌基因组中只有一个共享突变，表明两种遗传上不同的噬菌体的感染选择了不同的变体。这一知识为粪肠球菌在噬菌体感染期间的基因组进化的进一步研究提供了基础，并可用于指导未来治疗方法的设计，例如旨在靶向 MDR 粪肠球菌的噬菌体鸡尾酒。
