Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.
Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.
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DOI：
10.1016/j.molcel.2022.06.034
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发表时间：
2022-09-01
期刊：
影响因子：
16
通讯作者：
Ghosh, Pallavi
中科院分区：
文献类型：
--
作者：
Hurst-Hess, Kelley R.;Saxena, Aavrati;Rudra, Paulami;Yang, Yong;Ghosh, Pallavi
利福平（RIF）是抗支原体的一线药物。结核病，对M.部分原因是由于存在ADP-核糖基转移酶（Arr）使RIF失活。使用RNAseq，我们表明M.在实验室和临床分离株中，对亚致死剂量的RIF和Rifablavin（RBT）（RIF的一种类似物）的耐受导致Mab_helR上调约25倍。Mab_helR的同基因缺失导致RIF/RBT超敏反应，Mab_helR的过表达赋予M中的RIF耐受性。结核我们证明了在RIF暴露的细菌中增加的HelR-RNAP关联和MabHelR介导的RNAP从停滞的起始复合物中的体外解离。最后，我们表明，在RIF附近的Mab_helR的PCh环的尖端，是至关重要的赋予RIF抗性，但停滞RNAP复合物的解离，这表明HelR介导的RIF抗性需要一个步骤，除了RIF停滞RNAP的位移。结核分枝杆菌对利福平高度耐药。Hurst-Hess等人鉴定了利福平和利福平诱导基因helR，其缺失导致对两种利福平的超敏反应，并证明了HelR PCh环在耐药性中的关键作用，该环在RNA聚合酶内与利福平紧密结合。
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 RNAseq we show that exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close analogue of RIF, results in ~25-fold upregulation of Mab_helR in laboratory and clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT hypersensitivity and over-expression 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. Lastly, 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. Mycobacterium abscessus is highly resistant to rifampicin. Hurst-Hess et al identify a rifampicin and rifabutin inducible gene, helR, deletion of which results in hypersensitivity to both rifamycins, and demonstrate a critical role of the HelR PCh loop, that binds in close proximity to rifampicin within RNA polymerase, in resistance.
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