Department of Otolaryngology, Head and Neck Surgery, Stanford University, 801 Welch Road, Stanford, CA 94305-5739, USA.
Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China.
Nanoscale. 2022 Jul 21;14(28):10016-10032. doi: 10.1039/d2nr01003h.
Persister cells are responsible for relapses of infections common in cystic fibrosis and chronic suppurative otitis media (CSOM). Yet, there are no Food and Drug Administration (FDA) approved antibiotics to eradicate persister cells. Frustratingly, the global preclinical bacterial pipeline does not contain antibacterial agents targeting persister cells. Therefore, we report a nontraditional antimicrobial chemotherapy strategy based on gold nanoclusters adjuvant to eradicate persister cells by existing antibiotics belonging to that different class. Compared to killing with antibiotics alone, combining antibiotics and AuNC@CPP sterilizes persister cells and biofilms. Enhanced killing of up to 4 orders of magnitude in a validated mouse model of CSOM with infection was observed when combining antibiotics and AuNC@CPP, informing a potential approach to improve the treatment of CSOM. We established that the mechanism of action of AuNC@CPP is due to disruption of the proton gradient and membrane hyperpolarization. The method presented here could compensate for the lack of new antibiotics to combat persister cells. This method could also benefit the current effort to slow resistance development because AuNC@CPP abolished the emergence of drug-resistant strains induced by antibiotics.
持久细胞是导致囊性纤维化和慢性化脓性中耳炎（CSOM）等常见感染复发的罪魁祸首。然而，目前还没有获得美国食品和药物管理局（FDA）批准的抗生素来根除持久细胞。令人沮丧的是，全球临床前细菌管道中没有针对持久细胞的抗菌药物。因此，我们报告了一种基于金纳米簇的非传统抗菌化疗策略，该策略通过属于不同类别的现有抗生素来辅助根除持久细胞。与单独使用抗生素相比，抗生素和 AuNC@CPP 的组合可以杀死持久细胞和生物膜。在经过验证的 CSOM 感染小鼠模型中，观察到联合使用抗生素和 AuNC@CPP 可增强杀菌作用，高达 4 个数量级，为改善 CSOM 治疗提供了一种潜在方法。我们确定了 AuNC@CPP 的作用机制是由于质子梯度的破坏和膜超极化。这里提出的方法可以弥补缺乏新抗生素来对抗持久细胞的问题。由于 AuNC@CPP 消除了抗生素诱导的耐药菌株的出现，这种方法也可能有益于当前减缓耐药性发展的努力。
