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Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

Author:
Lin, Wei, Mandal, Soma, Degen, David, Liu, Yu, Ebright, Yon W., Li, Shengjian, Feng, Yu, Zhang, Yu, Mandal, Sukhendu, Jiang, Yi, Liu, Shuang, Gigliotti, Matthew, Talaue, Meliza, Connell, Nancy, Das, Kalyan, Arnold, Eddy, Ebright, Richard H.
Source:
Molecular cell 2017 v.66 no.2 pp. 169-179.e8
ISSN:
1097-2765
Subject:
DNA-directed RNA polymerase, Mycobacterium tuberculosis, RNA, crystal structure, drugs, rifampicin, transcription (genetics), tuberculosis
Abstract:
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually. Mtb RNA polymerase (RNAP) is the target of the first-line antituberculosis drug rifampin (Rif). We report crystal structures of Mtb RNAP, alone and in complex with Rif, at 3.8–4.4 Å resolution. The results identify an Mtb-specific structural module of Mtb RNAP and establish that Rif functions by a steric-occlusion mechanism that prevents extension of RNA. We also report non-Rif-related compounds—Nα-aroyl-N-aryl-phenylalaninamides (AAPs)—that potently and selectively inhibit Mtb RNAP and Mtb growth, and we report crystal structures of Mtb RNAP in complex with AAPs. AAPs bind to a different site on Mtb RNAP than Rif, exhibit no cross-resistance with Rif, function additively when co-administered with Rif, and suppress resistance emergence when co-administered with Rif.
Agid:
5674637