Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition
Richard H. Ebright,
Richard H. Ebright
Posted 10 Jan 2017
bioRxiv DOI: 10.1101/099606 (published DOI: 10.1016/j.molcel.2017.03.001)
Posted 10 Jan 2017
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--Nalpha-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.
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