利福霉素
结核分枝杆菌
聚合酶
RNA聚合酶
生物
病毒学
蛋白质亚单位
机制(生物学)
肺结核
RNA依赖性RNA聚合酶
微生物学
聚合酶链反应
遗传学
核糖核酸
抗生素
基因
医学
哲学
认识论
病理
作者
Maxwell Stefan,Fatima S. Ugur,George A. Garcia
摘要
ABSTRACT Mycobacterium tuberculosis is a critical threat to human health due to the increased prevalence of rifampin resistance (RMP r ). Fitness defects have been observed in RMP r mutants with amino acid substitutions in the β subunit of RNA polymerase (RNAP). In clinical isolates, this fitness defect can be ameliorated by the presence of secondary mutations in the double-psi β-barrel (DPBB) domain of the β′ subunit of RNAP. To identify factors contributing to the fitness defects observed in vivo , several in vitro RNA transcription assays were utilized to probe initiation, elongation, termination, and 3′-RNA hydrolysis with the wild-type and RMP r M. tuberculosis RNAPs. We found that the less prevalent RMP r mutants exhibit significantly poorer termination efficiencies relative to the wild type, an important factor for proper gene expression. We also found that several mechanistic aspects of transcription of the RMP r mutant RNAPs are impacted relative to the wild type. For the clinically most prevalent mutant, the βS450L mutant, these defects are mitigated by the presence of secondary/compensatory mutations in the DPBB domain of the β′ subunit.
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