Structural Basis of Mycobacterium Tuberculosis Transcription and Transcription Inhibition

Wei Lin, Soma Mandal, David Degen, Yu Liu, Yon W Ebright, Shengjian Li, Yu Feng, Yu Zhang, Sukhendu Mandal, Yi Jiang, Shuang Liu, Matthew Gigliotti, Meliza Talaue, Nancy Connell, Kalyan Das, Eddy Arnold, etc.

Mol Cell. 2017 Apr 20;66(2):169-179.e8.

PMID: 28392175

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP24570396	Nα,Nε-Diacetyl-Lys-D-Ala-D-Ala		24570-39-6	Price