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Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e00969-17. doi: 10.1128/AAC.00969-17. Print 2017 Nov.

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

Author information

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.
7
Eco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea iylee@krict.re.kr ramandeep@thsti.res.in.
8
Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India iylee@krict.re.kr ramandeep@thsti.res.in.

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.

KEYWORDS:

5-nitro-1,10-phenanthroline; F420 dependence; Mycobacterium tuberculosis; autophagy; phenotypic screening

PMID:
28893784
PMCID:
PMC5655107
DOI:
10.1128/AAC.00969-17
[Indexed for MEDLINE]
Free PMC Article

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