Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

Wei Lin, Soma Mandal, David Degen, Yu Liu, Yon W. Ebright, Shengjian Li, Yu Feng, Yu Zhang, Sukhendu Mandal, Yi Jiang, Shuang Liu, Matthew Gigliotti, Meliza Talaue, Nancy Connell, Kalyan Das, Eddy Arnold, Richard H. Ebright

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)169-179.e8
JournalMolecular cell
Volume66
Issue number2
DOIs
StatePublished - Apr 20 2017

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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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Lin, W., Mandal, S., Degen, D., Liu, Y., Ebright, Y. W., Li, S., Feng, Y., Zhang, Y., Mandal, S., Jiang, Y., Liu, S., Gigliotti, M., Talaue, M., Connell, N., Das, K., Arnold, E., & Ebright, R. H. (2017). Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition. Molecular cell, 66(2), 169-179.e8. https://doi.org/10.1016/j.molcel.2017.03.001