Buchieri Maria V, Cimino Mena, Rebollo-Ramirez Sonia, Beauvineau Claire, Cascioferro Alessandro, Favre-Rochex Sandrine, Helynck Olivier, Naud-Martin Delphine, Larrouy-Maumus Gerald, Munier-Lehmann Hélène, Gicquel Brigitte
Unité de Génétique Mycobactérienne, Institut Pasteur , 25 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
MRC Centre for Molecular Bacteriology & Infection, Imperial College London , London SW7 2AZ, United Kingdom.
J Med Chem. 2017 Sep 14;60(17):7425-7433. doi: 10.1021/acs.jmedchem.7b00726. Epub 2017 Aug 28.
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.
在本研究中，我们旨在解析分枝杆菌对基于全细胞的高通量筛选（HTS）分离出的新型化合物的天然抗性机制。我们使用金色分枝杆菌鉴定活性化合物。进一步分析以确定耻垢分枝杆菌对一种命中化合物3-溴-N-(5-硝基噻唑-2-基)-4-丙氧基苯甲酰胺（3）的抗性机制，结果发现其是药物硝唑尼特（1）的类似物。我们发现编码硝基还原酶NfnB的基因nfnB的抑制是耻垢分枝杆菌对3天然抗性的原因。nfnB的过表达导致耻垢分枝杆菌对3敏感。该化合物必须代谢为羟胺中间体才能表现出抗菌活性。因此，我们首次描述了分枝杆菌硝基还原酶对1类似物的活性，突出了分枝杆菌物种间硝基化合物代谢的差异，并强调了硝基药物作为各种细菌物种抗菌剂的潜力。
