Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

Author:

Kidwai Saqib1,Park Chan-Yong23,Mawatwal Shradha4,Tiwari Prabhakar1,Jung Myung Geun2,Gosain Tannu Priya1,Kumar Pradeep5,Alland David5,Kumar Sandeep6,Bajaj Avinash6,Hwang Yun-Kyung2,Song Chang Sik3,Dhiman Rohan4,Lee Ill Young2,Singh Ramandeep1

Affiliation:

1. Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India

2. Eco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea

3. Department of Chemistry, Sung Kyun Kwan University, Suwon, South Korea

4. Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India

5. Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Centre for the Study of Emerging and Reemerging Pathogens, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA

6. Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India

Abstract

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 F 420 -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.

Funder

Department of Biotechnology, Ministry of Science and Technology

Department of Science and Technology, Ministry of Science and Technology

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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