National Institute of Immunology, New Delhi, India.
Centre for Cellular and Molecular Biology, Hyderabad, India.
Elife. 2023 Jan 25;12:e75860. doi: 10.7554/eLife.75860.
The emergence of drug resistance in () is alarming and demands in-depth knowledge for timely diagnosis. We performed genome-wide association analysis using 2237 clinical strains of to identify novel genetic factors that evoke drug resistance. In addition to the known direct targets, we identified for the first time, a strong association between mutations in DNA repair genes and the multidrug-resistant phenotype. To evaluate the impact of variants identified in the clinical samples in the evolution of drug resistance, we utilized knockouts and complemented strains in and . Results show that variant mutations compromised the functions of MutY and UvrB. MutY variant showed enhanced survival compared with wild-type () when the strains were subjected to multiple rounds of ex vivo antibiotic stress. In an in vivo guinea pig infection model, the MutY variant outcompeted the wild-type strain. We show that novel variant mutations in the DNA repair genes collectively compromise their functions and contribute to better survival under antibiotic/host stress conditions.
（）中耐药性的出现令人震惊，需要深入了解以进行及时诊断。我们使用 2237 株临床分离株进行全基因组关联分析，以确定引发耐药性的新遗传因素。除了已知的直接靶点外，我们首次发现 DNA 修复基因的突变与多药耐药表型之间存在强烈关联。为了评估在临床样本中鉴定的变异对耐药性进化的影响，我们在 和 中利用基因敲除和互补菌株进行了研究。结果表明，突变变异削弱了 MutY 和 UvrB 的功能。当 菌株经历多轮体外抗生素压力时，MutY 变异株的存活能力比野生型（）更强。在体内豚鼠感染模型中，MutY 变异株胜过野生型菌株。我们表明，DNA 修复基因中的新型变异突变共同削弱了它们的功能，并有助于在抗生素/宿主应激条件下更好地存活。
