生物
利福平
利福霉素
RNA聚合酶
结核分枝杆菌
利福平
微生物学
聚合酶
核糖核酸
脓肿分枝杆菌
病毒学
分子生物学
作者
Kelley R. Hurst-Hess,Aavrati Saxena,Paulami Rudra,Yong Yang,Pallavi Ghosh
出处
期刊:Molecular Cell
[Elsevier]
日期:2022-07-01
卷期号:82 (17): 3166-3177.e5
标识
DOI:10.1016/j.molcel.2022.06.034
摘要
Summary
Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in M. tuberculosis. We demonstrate an increased HelR-RNAP association in RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance but dispensable for dissociation of stalled RNAP complexes, suggesting that HelR-mediated RIF resistance requires a step in addition to displacement of RIF-stalled RNAP.
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