Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India.
Eco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea.
Antimicrob Agents Chemother. 2017 Oct 24;61(11). doi: 10.1128/AAC.00969-17. Print 2017 Nov.
New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved activity and efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against , 5NP also modulates the host machinery to kill intracellular pathogens.
需要新型作用机制的新型化疗药物来应对耐药分枝杆菌出现带来的挑战。在这项研究中，表型全细胞筛选发现 5-硝基-1,10-菲咯啉（5NP）是一种先导化合物。5NP 抗性分离株携带的突变被定位到，并对双环硝基咪唑 PA-824 也有抗性。机制研究证实 5NP 以 F 依赖性方式被激活，导致 1,10-菲咯啉和 1,10-菲咯啉-5-胺形成主要代谢物。有趣的是，5NP 通过诱导巨噬细胞自噬也能杀死天然耐药的细胞内细菌。构效关系研究表明，硝基对 活性是必需的，一种类似物 3-甲基-6-硝基-1,10-菲咯啉，与 5NP 相比，具有更好的 活性和在小鼠中的疗效。这些发现表明，除了对 有直接作用机制外，5NP 还调节宿主机制以杀死细胞内病原体。
