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Mechanisms of Action: Physiological Effects

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
Saqib Kidwai
aVaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Chan-Yong Park
bEco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea
cDepartment of Chemistry, Sung Kyun Kwan University, Suwon, South Korea
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Shradha Mawatwal
dLaboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
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Prabhakar Tiwari
aVaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Myung Geun Jung
bEco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea
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Tannu Priya Gosain
aVaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Pradeep Kumar
eDivision 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
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David Alland
eDivision 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
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Sandeep Kumar
fLaboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Avinash Bajaj
fLaboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Yun-Kyung Hwang
bEco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea
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Chang Sik Song
cDepartment of Chemistry, Sung Kyun Kwan University, Suwon, South Korea
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Rohan Dhiman
dLaboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
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Ill Young Lee
bEco-Friendly New Materials Research Centre, Korean Research Institute of Chemical Technology, Daejeon, South Korea
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Ramandeep Singh
aVaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
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DOI: 10.1128/AAC.00969-17
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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.

FOOTNOTES

    • Received 10 May 2017.
    • Returned for modification 29 May 2017.
    • Accepted 25 August 2017.
    • Accepted manuscript posted online 11 September 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00969-17 .

  • Copyright © 2017 American Society for Microbiology.

All Rights Reserved .

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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
Antimicrobial Agents and Chemotherapy Oct 2017, 61 (11) e00969-17; DOI: 10.1128/AAC.00969-17

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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
Antimicrobial Agents and Chemotherapy Oct 2017, 61 (11) e00969-17; DOI: 10.1128/AAC.00969-17
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KEYWORDS

antitubercular agents
autophagy
Mycobacterium tuberculosis
Phenanthrolines
Tuberculosis, Multidrug-Resistant
5-nitro-1,10-phenanthroline
autophagy
F420 dependence
Mycobacterium tuberculosis
phenotypic screening

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