PT  - JOURNAL ARTICLE
AU  - Wei Lin
AU  - Soma Mandal
AU  - David Degen
AU  - Yu Liu
AU  - Yon W. Ebright
AU  - Shengjian Li
AU  - Yu Feng
AU  - Yu Zhang
AU  - Sukhendu Mandal
AU  - Yi Jiang
AU  - Shuang Liu
AU  - Matthew Gigliotti
AU  - Meliza Talaue
AU  - Nancy Connell
AU  - Kalyan Das
AU  - Eddy Arnold
AU  - Richard H. Ebright
TI  - Structural basis of <em>Mycobacterium tuberculosis</em> transcription and transcription inhibition
AID  - 10.1101/099606
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 099606
4099  - http://biorxiv.org/content/early/2017/01/10/099606.short
4100  - http://biorxiv.org/content/early/2017/01/10/099606.full
AB  - One Sentence Summary Structures of Mycobacterium tuberculosis RNA polymerase reveal taxon-specific properties and binding sites of known and new antituberculosis agentsAbstract 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. 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 novel 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.