Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.
Mol Cell
; 82(17): 3166-3177.e5, 2022 09 01.
Article
em En
| MEDLINE
| ID: mdl-35905736
ABSTRACT
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 â¼25-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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Base de dados:
MEDLINE
Assunto principal:
Rifamicinas
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Tuberculose
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Mycobacterium abscessus
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Mycobacterium tuberculosis
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article