State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
Shenzhen Key Lab of Food Microbial Safety Control, The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
Microb Biotechnol. 2024 Nov;17(11):e70042. doi: 10.1111/1751-7915.70042.
Bacterial antibiotic tolerance is a decades-old phenomenon in which a bacterial sub-population, commonly known as persisters, does not respond to antibiotics and remains viable upon prolonged antimicrobial treatment. Persisters are detectable in populations of bacterial strains that are not antibiotic-resistant and are known to be responsible for treatment failure and the occurrence of chronic and recurrent infection. The clinical significance of antibiotic tolerance is increasingly being recognized and comparable to antibiotic resistance. To eradicate persisters, it is necessary to understand the cellular mechanisms underlying tolerance development. Previous works showed that bacterial antibiotic tolerance was attributed to the reduction in metabolic activities and activation of the stringent response, SOS response and the toxin-antitoxin system which down-regulates transcription functions. The latest research findings, however, showed that decreased metabolic activities alone do not confer a long-lasting tolerance phenotype in persisters, and that active defence mechanisms such as efflux and DNA repair are required for the long-term maintenance of phenotypic tolerance. As such active tolerance-maintenance mechanisms are energy-demanding, persisters need to generate and maintain the transmembrane proton motive force (PMF) for oxidative phosphorylation. This minireview summarizes the current understanding of cellular mechanisms essential for prolonged expression of phenotypic antibiotic tolerance in bacteria, with an emphasis on the importance of generation and maintenance of PMF in enabling proper functioning of the active tolerance mechanisms in persisters. How such mechanisms can be utilized as targets for the development of anti-persister strategies will be discussed.
细菌抗生素耐受是一个存在了几十年的现象，在这个现象中，一个细菌亚群，通常被称为持留菌，不会对抗生素产生反应，并在长时间的抗菌治疗后仍然存活。持留菌在没有抗生素耐药性的细菌菌株群体中是可以检测到的，它们被认为是导致治疗失败和慢性、复发性感染的原因。抗生素耐受的临床意义越来越受到重视，其重要性可与抗生素耐药性相媲美。为了消灭持留菌，有必要了解导致耐受发展的细胞机制。以前的研究表明，细菌抗生素耐受归因于代谢活性的降低和严格反应、SOS 反应和毒素-抗毒素系统的激活，这些反应会下调转录功能。然而，最新的研究结果表明，代谢活性的降低本身并不能赋予持留菌持久的耐受表型，需要主动的防御机制，如外排和 DNA 修复，才能长期维持表型耐受。由于这种主动的耐受维持机制需要能量，因此持留菌需要产生并维持跨膜质子动力势（PMF）以进行氧化磷酸化。本综述总结了目前对细菌中表型抗生素耐受长期表达所必需的细胞机制的理解，重点强调了在持留菌中，PMF 的产生和维持对于主动耐受机制正常运作的重要性。我们将讨论如何利用这些机制作为开发抗持留菌策略的靶点。
