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

Saqib Kidwai; Chan-Yong Park; Shradha Mawatwal; Prabhakar Tiwari; Myung Geun Jung; Tannu Priya Gosain; Pradeep Kumar; David Alland; Sandeep Kumar; Avinash Bajaj; Yun-Kyung Hwang; Chang Sik Song; Rohan Dhiman; Ill Young Lee; Ramandeep Singh

doi:10.1128/AAC.00969-17

Back

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

Journal article

Open access

Peer reviewed

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

Saqib Kidwai, Chan-Yong Park, Shradha Mawatwal, Prabhakar Tiwari, Myung Geun Jung, Tannu Priya Gosain, Pradeep Kumar, David Alland, Sandeep Kumar, Avinash Bajaj, …

Antimicrobial agents and chemotherapy, Vol.61(11)

11/2017

DOI: https://doi.org/10.1128/AAC.00969-17

PMCID: PMC5655107

PMID: 28893784

Abstract

Nitroimidazoles - pharmacology

Escherichia coli - drug effects

Humans

Antitubercular Agents - pharmacology

THP-1 Cells

Structure-Activity Relationship

Mycobacterium tuberculosis - drug effects

Autophagy - drug effects

Mycobacterium tuberculosis - isolation & purification

Microbial Sensitivity Tests

Mycobacterium bovis - drug effects

Macrophages - metabolism

Animals

Phenanthrolines - pharmacology

Mycobacterium smegmatis - drug effects

Cell Line, Tumor

Female

Mice

Mice, Inbred BALB C

Macrophages - microbiology

Disease Models, Animal

Mycobacterium tuberculosis - genetics

Mycobacterium tuberculosis - growth & development

Tuberculosis, Multidrug-Resistant - drug therapy

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.

Files and links (1)

url

https://doi.org/10.1128/AAC.00969-17View

Version of Record (VoR) Open

Metrics

10 Record Views

29 Times Cited - Web of Science

See more details

Details

Title: Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis
Creators: Saqib Kidwai - Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Chan-Yong Park - Department of Chemistry, Sung Kyun Kwan University, Suwon, South Korea
Shradha Mawatwal - Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
Prabhakar Tiwari - Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Myung Geun Jung - Eco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea
Tannu Priya Gosain - Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Pradeep Kumar - 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
David Alland - 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
Sandeep Kumar - Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India
Avinash Bajaj - Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India
Yun-Kyung Hwang - Eco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea
Chang Sik Song - Department of Chemistry, Sung Kyun Kwan University, Suwon, South Korea
Rohan Dhiman - Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
Ill Young Lee - Eco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea iylee@krict.re.kr ramandeep@thsti.res.in
Ramandeep Singh - 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
Publication Details: Antimicrobial agents and chemotherapy, Vol.61(11)
Date published: 11/2017
Academic Unit: Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031653988904646