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Nitazoxanide Analogs Require Nitroreduction for Antimicrobial Activity in Mycobacterium smegmatis
Maria V Buchieri1, Mena Cimino1, Sonia Rebollo-Ramirez2
1Unité de Génétique Mycobactérienne, Institut Pasteur , 25 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
Journal of Medicinal Chemistry
|August 29, 2017
Summary
Mycobacterium smegmatis naturally resists a novel nitazoxanide analog due to nitroreductase NfnB. Overexpressing this enzyme increases sensitivity, revealing a key drug metabolism pathway for developing new mycobacterial treatments.
Area of Science:
- Microbiology
- Drug Discovery
- Biochemistry
Background:
- Mycobacteria exhibit natural resistance to antimicrobial compounds.
- High-throughput screening (HTS) is crucial for identifying novel drug candidates.
- Understanding resistance mechanisms is key to developing effective treatments.
Purpose of the Study:
- To investigate natural resistance mechanisms in mycobacteria against novel compounds.
- To identify the specific gene and protein responsible for resistance to a nitazoxanide analog.
- To elucidate the metabolic pathway required for the compound's antibacterial activity.
Main Methods:
- Whole-cell-based high-throughput screening (HTS) using Mycobacterium aurum.
- Resistance mechanism analysis in Mycobacterium smegmatis against compound 3 (a nitazoxanide analog).
- Gene knockout and overexpression studies focusing on the nfnB gene encoding nitroreductase NfnB.
Main Results:
- Identification of 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide as a compound with activity against mycobacteria.
- Repression of the nfnB gene confers natural resistance in M. smegmatis.
- Overexpression of nfnB leads to increased sensitivity to the compound, indicating NfnB's role in metabolism.
- The compound requires metabolism into a hydroxylamine intermediate for antibacterial action.
Conclusions:
- Nitroreductase NfnB plays a critical role in the natural resistance of M. smegmatis to a nitazoxanide analog.
- Metabolism of nitro compounds by mycobacterial nitroreductases is species-specific.
- Nitro drugs show potential as antibacterials across various bacterial species, pending understanding of their metabolic activation.
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