Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition

One Sentence Summary Structures of Mycobacterium tuberculosis RNA polymerase reveal taxon-specific properties and binding sites of known and new antituberculosis agents 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. 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.