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.
[Display omitted]
•Crystal structures of Mycobacterium tuberculosis RNA polymerase (Mtb RNAP)•Crystal structures of Mtb RNAP in complex with antituberculosis drug rifampin•Crystal structures of Mtb RNAP in complex with new antituberculosis compound D-AAP1•Different binding sites and simultaneous binding of rifampin and D-AAP1
Lin et al. report crystal structures of Mycobacterium tuberculosis RNA polymerase, alone and in complex with the antituberculosis compounds rifampin and D-AAP1. D-AAP1 interacts with a different binding site than rifampin, exhibits no cross-resistance with rifampin, functions additively when co-administered with rifampin, and suppresses resistance emergence when co-administered with rifampin.