Center for Microbiology, VIB, 3001 Leuven, Belgium; Centre of Microbial and Plant Genetics, KU Leuven, 3001 Leuven, Belgium.
Centre of Microbial and Plant Genetics, KU Leuven, 3001 Leuven, Belgium.
Cell Rep. 2022 Mar 1;38(9):110427. doi: 10.1016/j.celrep.2022.110427.
Persisters constitute a population of temporarily antibiotic-tolerant variants in an isogenic bacterial population and are considered an important cause of relapsing infections. It is currently unclear how cellular damage inflicted by antibiotic action is reversed upon persister state exit and how this relates to antibiotic resistance development at the molecular level. We demonstrate that persisters, upon fluoroquinolone treatment, accumulate oxidative DNA damage, which is repaired through nucleotide excision repair. Detection of the damage occurs via transcription-coupled repair using UvrD-mediated backtracking or Mfd-controlled displacement of the RNA polymerase. This competition results in heterogeneity in persister awakening lags. Most persisters repair the oxidative DNA damage, displaying a mutation rate equal to the untreated population. However, the promutagenic factor Mfd increases the mutation rate in a persister subpopulation. Our data provide in-depth insight into the molecular mechanisms underlying persister survival and pinpoint Mfd as an important molecular factor linking persistence to resistance development.
持留菌是同种细菌群体中暂时对抗生素耐受的变异体种群，被认为是反复感染的一个重要原因。目前尚不清楚抗生素作用造成的细胞损伤在持留状态退出时如何被逆转，以及这与分子水平的抗生素耐药性发展有何关系。我们证明，持留菌在氟喹诺酮类药物治疗时会积累氧化 DNA 损伤，这种损伤可通过核苷酸切除修复来修复。通过 UvrD 介导的回溯或 Mfd 控制的 RNA 聚合酶置换来使用转录偶联修复来检测损伤。这种竞争导致持留菌苏醒滞后的异质性。大多数持留菌修复了氧化 DNA 损伤，其突变率与未处理的群体相同。然而，诱变因素 Mfd 会增加持留菌亚群的突变率。我们的数据深入了解了持留菌存活的分子机制，并指出 Mfd 是将持留与耐药性发展联系起来的一个重要分子因素。
