Bekale Laurent A, Sharma Devesh, Bacacao Brian, Chen Jing, Santa Maria Peter L
Department of Otolaryngology, Head and Neck Surgery, Stanford University, 801 Welch Road Stanford, CA 94305-5739, USA.
Nano Today. 2023 Aug;51. doi: 10.1016/j.nantod.2023.101895. Epub 2023 Jun 12.
Bacteria first develop tolerance after antibiotic exposure; later genetic resistance emerges through the population of tolerant bacteria. Bacterial persister cells are the multidrug-tolerant subpopulation within an isogenic bacteria culture that maintains genetic susceptibility to antibiotics. Because of this link between antibiotic tolerance and resistance and the rise of antibiotic resistance, there is a pressing need to develop treatments to eradicate persister cells. Current anti persister cell strategies are based on the paradigm of "awakening" them from their low metabolic state before attempting eradication with traditional antibiotics. Herein, we demonstrate that the low metabolic activity of persister cells can be exploited for eradication over their metabolically active counterparts. We engineered gold nanoclusters coated with adenosine triphosphate (AuNC@ATP) as a benchmark nanocluster that kills persister cells over exponential growth bacterial cells and prove the feasibility of this new concept. Finally, using AuNC@ATP as a new research tool, we demonstrated that it is possible to prevent the emergence of antibiotic-resistant superbugs with an anti-persister compound. Eradicating persister cells with AuNC@ATP in an isogenic culture of bacteria stops the emergence of superbug bacteria mediated by the sub-lethal dose of conventional antibiotics. Our findings lay the groundwork for developing novel nano-antibiotics targeting persister cells, which promise to prevent the emergence of superbugs and prolong the lifespan of currently available antibiotics.
细菌在接触抗生素后首先产生耐受性；随后，通过耐受性细菌群体出现遗传抗性。细菌持留细胞是同基因细菌培养物中的多药耐受性亚群，对抗生素保持遗传敏感性。由于抗生素耐受性与抗性之间的这种联系以及抗生素抗性的增加，迫切需要开发根除持留细胞的治疗方法。当前的抗持留细胞策略基于在尝试用传统抗生素根除之前将它们从低代谢状态“唤醒”的范式。在此，我们证明可以利用持留细胞的低代谢活性来根除它们代谢活跃的对应细胞。我们设计了涂有三磷酸腺苷的金纳米团簇（AuNC@ATP）作为一种基准纳米团簇，它能杀死处于指数生长期的细菌细胞中的持留细胞，并证明了这一新概念的可行性。最后，使用AuNC@ATP作为一种新的研究工具，我们证明了用一种抗持留化合物有可能预防抗生素抗性超级细菌的出现。在同基因细菌培养物中用AuNC@ATP根除持留细胞可阻止由亚致死剂量的传统抗生素介导的超级细菌的出现。我们的发现为开发针对持留细胞的新型纳米抗生素奠定了基础，有望预防超级细菌的出现并延长现有抗生素的使用寿命。
