Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Dr., Gainesville, FL 32610 (USA).
Department of Molecular Genetics & Microbiology, University of Florida (USA).
Angew Chem Int Ed Engl. 2015 Dec 1;54(49):14819-23. doi: 10.1002/anie.201508155. Epub 2015 Oct 20.
Conventional antibiotics are ineffective against non-replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1, that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC = 0.2-12.5 μM), as well as the effective killing of MRSA persister cells in non-biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non-biofilm persisters alongside 14. HP 13 displayed potent antibacterial activity against slow-growing M. tuberculosis (MIC = 3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non-toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.
传统抗生素对非复制细菌（例如生物膜内的细菌）无效。我们报告了一系列受海洋抗生素 1 启发的卤化苯并嗪（HP），它们针对持久性细菌。HP14 对 MRSA、MRSE 和 VRE 生物膜表现出迄今为止最有效的生物膜清除活性（MBEC=0.2-12.5 μM），并且能够有效杀死非生物膜培养物中的 MRSA 持续存在细胞。一线 MRSA 治疗药物万古霉素和达托霉素无法与 14 一起根除 MRSA 生物膜或非生物膜持续存在细胞。HP13 对生长缓慢的结核分枝杆菌（MIC=3.13 μM）显示出强大的抗菌活性，这是全球细菌性感染导致死亡的主要原因。HP 类似物通过对哺乳动物细胞无毒的机制有效靶向持续性细菌，这可能对慢性细菌感染的治疗产生重大影响。
