Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition.
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.
['Lin|Wei|W|', 'Mandal|Soma|S|', 'Degen|David|D|', 'Liu|Yu|Y|', 'Ebright|Yon W|YW|', 'Li|Shengjian|S|', 'Feng|Yu|Y|', 'Zhang|Yu|Y|', 'Mandal|Sukhendu|S|', 'Jiang|Yi|Y|', 'Liu|Shuang|S|', 'Gigliotti|Matthew|M|', 'Talaue|Meliza|M|', 'Connell|Nancy|N|', 'Das|Kalyan|K|', 'Arnold|Eddy|E|', 'Ebright|Richard H|RH|']
D000995:Antitubercular Agents D001426:Bacterial Proteins D001665:Binding Sites D012321:DNA-Directed RNA Polymerases D024881:Drug Resistance, Bacterial D004791:Enzyme Inhibitors D015964:Gene Expression Regulation, Bacterial D008958:Models, Molecular D009169:Mycobacterium tuberculosis D011485:Protein Binding D011487:Protein Conformation D012293:Rifampin D013329:Structure-Activity Relationship D014158:Transcription, Genetic
RNA polymerase rifampin AAPs D-AAP1 Nα-aroyl-N-aryl-phenylalaninamides RNA polymerase inhibitors RNA polymerase-promoter initial transcribing complex RNA polymerase-promoter open complex antituberculosis agents promoter sigma factor