Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, New York, United States of America.
Department of Biological Sciences, Binghamton University, Binghamton, New York, United States of America.
PLoS Pathog. 2021 Dec 10;17(12):e1010144. doi: 10.1371/journal.ppat.1010144. eCollection 2021 Dec.
Persistent bacterial infections do not respond to current antibiotic treatments and thus present a great medical challenge. These conditions have been linked to the formation of dormant subpopulations of bacteria, known as persister cells, that are growth-arrested and highly tolerant to conventional antibiotics. Here, we report a new strategy of persister control and demonstrate that minocycline, an amphiphilic antibiotic that does not require active transport to penetrate bacterial membranes, is effective in killing Escherichia coli persister cells [by 70.8 ± 5.9% (0.53 log) at 100 μg/mL], while being ineffective in killing normal cells. Further mechanistic studies revealed that persister cells have reduced drug efflux and accumulate more minocycline than normal cells, leading to effective killing of this dormant subpopulation upon wake-up. Consistently, eravacycline, which also targets the ribosome but has a stronger binding affinity than minocycline, kills persister cells by 3 logs when treated at 100 μg/mL. In summary, the findings of this study reveal that while dormancy is a well-known cause of antibiotic tolerance, it also provides an Achilles' heel for controlling persister cells by leveraging dormancy associated reduction of drug efflux.
持续性细菌感染对当前的抗生素治疗没有反应，因此构成了巨大的医学挑战。这些情况与休眠亚群细菌（称为持留细胞）的形成有关，持留细胞处于生长停滞状态，对常规抗生素具有高度耐受性。在这里，我们报告了一种新的持留控制策略，并证明了米诺环素（一种不需要主动转运即可穿透细菌膜的两亲性抗生素）在杀死大肠杆菌持留细胞方面非常有效[在 100μg/mL 时有效率为 70.8±5.9%（0.53 log）]，而对正常细胞无效。进一步的机制研究表明，持留细胞的药物外排减少，并且比正常细胞积累更多的米诺环素，从而在唤醒时有效地杀死这种休眠亚群。一致地，依拉环素（同样靶向核糖体，但与米诺环素的结合亲和力更强）在 100μg/mL 时处理时可将持留细胞杀灭 3 个对数级。总之，这项研究的结果表明，虽然休眠是抗生素耐药性的一个众所周知的原因，但它也为通过利用与休眠相关的药物外排减少来控制持留细胞提供了一个阿喀琉斯之踵。
