title: Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition.
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.
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: David
authors.initials: D
authors.lastname: Degen
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Yon W
authors.initials: YW
authors.lastname: Ebright
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Sukhendu
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gigliotti
authors.affiliation: Center for Biodefense and Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07101, USA.
authors.forename: Meliza
authors.initials: M
authors.lastname: Talaue
authors.affiliation: Center for Biodefense and Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07101, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Connell
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.affiliation: Waksman Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: ebright@waksman.rutgers.edu.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ebright
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin
keywords: AAPs; D-AAP1; Nα-aroyl-N-aryl-phenylalaninamides; RNA polymerase; RNA polymerase inhibitors; RNA polymerase-promoter initial transcribing complex; RNA polymerase-promoter open complex; antituberculosis agents; promoter; rifampin; sigma factor