1. Nitazoxanide Analogs Require Nitroreduction for Antimicrobial Activity in Mycobacterium smegmatis
- Author
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Gerald Larrouy-Maumus, Sandrine Favre-Rochex, Alessandro Cascioferro, Hélène Munier-Lehmann, Sonia Rebollo-Ramirez, Claire Beauvineau, Delphine Naud-Martin, Mena Cimino, Brigitte Gicquel, Maria Virginia Buchieri, Olivier Helynck, Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris], Imperial College London, Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée, Chimie et Biocatalyse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work is part of the European Seventh Framework Program Nanotherapeutics against Resistant Emerging Bacterial Pathogens (NAREB Project 604237). This work was also supported by the 'Programme de Recherche sur les Nouvelles Molécules Intervenant dans la Lutte Contre la Tuberculose' of the Gabonese Republic, the Department of Life Sciences and the Faculty of Natural Sciences kick-start funding award from Imperial College London, U.K., and Agilent Technologies, U.K., concerning all LC–MS experiments performed on the Agilent 6545 QToF., We thank Yves Janin for fruitful discussions and technical support., European Project: 604237,EC:FP7:NMP,FP7-NMP-2013-LARGE-7,NAREB(2014), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Mycobacterium smegmatis ,030106 microbiology ,Down-Regulation ,Mycobacterium Infections, Nontuberculous ,MESH: Thiazoles ,MESH: Down-Regulation ,Mycobacterium aurum ,Mycobacterium ,Microbiology ,03 medical and health sciences ,Nitroreductase ,chemistry.chemical_compound ,Hydroxylamine ,MESH: Anti-Bacterial Agents ,Drug Resistance, Bacterial ,MESH: Drug Resistance, Bacterial ,Drug Discovery ,MESH: Mycobacterium ,medicine ,Humans ,[CHIM]Chemical Sciences ,MESH: Mycobacterium Infections ,Gene ,MESH: Mycobacterium smegmatis ,Mycobacterium Infections ,MESH: Humans ,biology ,Nitazoxanide ,Nitroreductases ,Nitro Compounds ,MESH: Mycobacterium Infections, Nontuberculous ,Antimicrobial ,biology.organism_classification ,Anti-Bacterial Agents ,3. Good health ,Thiazoles ,MESH: Nitroreductases ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,030104 developmental biology ,chemistry ,Biochemistry ,Molecular Medicine ,Antibacterial activity ,medicine.drug - Abstract
International audience; In this study, we aimed to decipher the natural resistance mechanisms of mycobacteria against novel compounds isolated by whole-cell-based high-throughput screening (HTS). We identified active compounds using Mycobacterium aurum. Further analyses were performed to determine the resistance mechanism of M. smegmatis against one hit, 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide (3), which turned out to be an analog of the drug nitazoxanide (1). We found that the repression of the gene nfnB coding for the nitroreductase NfnB was responsible for the natural resistance of M. smegmatis against 3. The overexpression of nfnB resulted in sensitivity of M. smegmatis to 3. This compound must be metabolized into hydroxylamine intermediate for exhibiting antibacterial activity. Thus, we describe, for the first time, the activity of a mycobacterial nitroreductase against 1 analogs, highlighting the differences in the metabolism of nitro compounds among mycobacterial species and emphasizing the potential of nitro drugs as antibacterials in various bacterial species.
- Published
- 2017
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