Kidwai, Saqib and Park, Chan-Yong and Mawatwal, Shradha and Tiwari, Prabhakar and Jung, Myung Geun and Gosain, Tannu Priya and Kumar, Pradeep and Alland, David and Kumar, Sandeep and Bajaj, Avinash and Hwang, Yun-Kyung and Song, Chang Sik and Dhiman, Rohan and Lee, Ill Young and Singh, Ramandeep (2017) Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 61 (11). ISSN 0066-4804

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Abstract

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 fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-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 in vitro activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens.

Item Type:	Article
Subjects:	Biomedical Science Bioengineering & Devices
Depositing User:	RCB Library
Date Deposited:	17 Jul 2020 12:11
Last Modified:	17 Jul 2020 12:11
URI:	http://rcb.sciencecentral.in/id/eprint/353

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