| Literature DB >> 28392175 |
Wei Lin1, Soma Mandal1, David Degen1, Yu Liu1, Yon W Ebright1, Shengjian Li1, Yu Feng1, Yu Zhang1, Sukhendu Mandal1, Yi Jiang1, Shuang Liu1, Matthew Gigliotti1, Meliza Talaue2, Nancy Connell2, Kalyan Das3, Eddy Arnold3, Richard H Ebright4.
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.Entities:
Keywords: AAPs; D-AAP1; Nα-aroyl-N-aryl-phenylalaninamides; RNA polymerase; RNA polymerase inhibitors; RNA polymerase-promoter initial transcribing complex; RNA polymerase-promoter open complex; antituberculosis agents; promoter; rifampin; sigma factor
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Year: 2017 PMID： 28392175 PMCID： PMC5438085 DOI： 10.1016/j.molcel.2017.03.001
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970