دورية أكاديمية
Source of the Fitness Defect in Rifamycin-Resistant Mycobacterium tuberculosis RNA Polymerase and the Mechanism of Compensation by Mutations in the β' Subunit.
| العنوان: | Source of the Fitness Defect in Rifamycin-Resistant Mycobacterium tuberculosis RNA Polymerase and the Mechanism of Compensation by Mutations in the β' Subunit. |
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| المؤلفون: | Stefan MA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA., Ugur FS; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA., Garcia GA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA gagarcia@umich.edu. |
| المصدر: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2018 May 25; Vol. 62 (6). Date of Electronic Publication: 2018 May 25 (Print Publication: 2018). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother |
| أسماء مطبوعة: | Original Publication: Washington, American Society for Microbiology |
| مواضيع طبية MeSH: | DNA-Directed RNA Polymerases/*genetics , Drug Resistance, Multiple, Bacterial/*genetics , Genetic Fitness/*genetics , Mycobacterium tuberculosis/*drug effects , Mycobacterium tuberculosis/*genetics , Peptide Chain Elongation, Translational/*genetics , Rifampin/*pharmacology , Rifamycins/*pharmacology, Amino Acid Sequence/genetics ; Amino Acid Substitution/genetics ; Humans ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/isolation & purification ; Peptide Chain Termination, Translational/genetics ; Protein Domains/genetics ; Tuberculosis, Pulmonary/drug therapy ; Tuberculosis, Pulmonary/microbiology |
| مستخلص: | 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. (Copyright © 2018 American Society for Microbiology.) |
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| معلومات مُعتمدة: | R01 AI110780 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: RNA polymerase kinetics; antibiotic resistance; tuberculosis |
| المشرفين على المادة: | 0 (Rifamycins) EC 2.7.7.6 (DNA-Directed RNA Polymerases) VJT6J7R4TR (Rifampin) |
| تواريخ الأحداث: | Date Created: 20180418 Date Completed: 20190819 Latest Revision: 20190819 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC5971562 |
| DOI: | 10.1128/AAC.00164-18 |
| PMID: | 29661864 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-6596 |
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| DOI: | 10.1128/AAC.00164-18 |