Abstract

The purpose of the present study was to evaluate the association of mutations inside and outside quinolone-resistance determining region (QRDR) of gyrA gene with resistance to fluoroquinolones, particularly levofloxacin (LFX), moxifloxacin (MFX), ofloxacin (OFX), and ciprofloxacin (CIP). Therefore, a total of 255 clinical isolates of Mycobacterium tuberculosis were tested for drug susceptibility. Accordingly, 68 multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis strains were subjected to molecular analysis. Mutations were found in 25 (43.1%) of fluoroquinolone-resistant isolates including two rare mutations at codons 93 and 124. We then proceeded to predict the functional and structural impacts of the identified mutations on the protein via PredictSNP, PROVEAN, PoPMuSiC, and HoTMuSiC tools which revealed that they could be deleterious and/or destabilizing to GyrA. Our findings suggest that coupling genetic analysis with computational approaches could be of great value for unraveling molecular mechanisms involved in drug resistance.

中文翻译：

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多重耐药结核分枝杆菌临床分离株中gyrA基因突变与氟喹诺酮类药物耐药的关联

摘要

本研究的目的是评估gyrA基因喹诺酮耐药决定区（QRDR）内部和外部的突变与氟喹诺酮类药物，特别是左氧氟沙星（LFX）、莫西沙星（MFX）、氧氟沙星（OFX）和环丙沙星耐药的关联。 (CIP)。因此，总共对255株结核分枝杆菌临床分离株进行了药敏试验。因此，对 68 种多重耐药 (MDR) 和广泛耐药 (XDR) 结核菌株进行了分子分析。在 25 种 (43.1%) 氟喹诺酮耐药分离株中发现突变，其中包括密码子 93 和 124 处的两个罕见突变。然后，我们通过 PredictSNP、PROVEAN、PoPMuSiC 和 HoTMuSiC 预测已识别突变对蛋白质的功能和结构影响这些工具显示它们可能对 GyrA 有害和/或不稳定。我们的研究结果表明，将遗传分析与计算方法相结合对于揭示耐药性的分子机制具有重要价值。