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Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition.

Lin W, Mandal S, Degen D, Liu Y, Ebright YW, Li S, Feng Y, Zhang Y, Mandal S, Jiang Y, Liu S, Gigliotti M, Talaue M, Connell N, Das K, Arnold E, Ebright RH
Mol Cell 66 169-179.e8 (2017)
Related entries: 5uh5, 5uh6, 5uh7, 5uh8, 5uh9, 5uhb, 5uhc, 5uhd, 5uhe, 5uhf, 5uhg

Cited: 75 times
EuropePMC logo PMID: 28392175

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.

Articles - 5uha mentioned but not cited (7)

  1. Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition. Lin W, Mandal S, Degen D, Liu Y, Ebright YW, Li S, Feng Y, Zhang Y, Mandal S, Jiang Y, Liu S, Gigliotti M, Talaue M, Connell N, Das K, Arnold E, Ebright RH. Mol Cell 66 169-179.e8 (2017)
  2. Structural basis for transcription initiation by bacterial ECF σ factors. Li L, Fang C, Zhuang N, Wang T, Zhang Y. Nat Commun 10 1153 (2019)
  3. Structural insights into the mycobacteria transcription initiation complex from analysis of X-ray crystal structures. Hubin EA, Lilic M, Darst SA, Campbell EA. Nat Commun 8 16072 (2017)
  4. Structural basis of ECF-σ-factor-dependent transcription initiation. Lin W, Mandal S, Degen D, Cho MS, Feng Y, Das K, Ebright RH. Nat Commun 10 710 (2019)
  5. Source of the Fitness Defect in Rifamycin-Resistant Mycobacterium tuberculosis RNA Polymerase and the Mechanism of Compensation by Mutations in the β' Subunit. Stefan MA, Ugur FS, Garcia GA. Antimicrob Agents Chemother 62 e00164-18 (2018)
  6. Visualization of two architectures in class-II CAP-dependent transcription activation. Shi W, Jiang Y, Deng Y, Dong Z, Liu B. PLoS Biol 18 e3000706 (2020)
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Reviews citing this publication (12)

  1. Diverse and unified mechanisms of transcription initiation in bacteria. Chen J, Boyaci H, Campbell EA. Nat Rev Microbiol 19 95-109 (2021)
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  5. Transcription initiation in mycobacteria: a biophysical perspective. Boyaci H, Saecker RM, Campbell EA. Transcription 11 53-65 (2020)
  6. Discovery, properties, and biosynthesis of pseudouridimycin, an antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. Maffioli SI, Sosio M, Ebright RH, Donadio S. J Ind Microbiol Biotechnol 46 335-343 (2019)
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  8. M. tuberculosis Transcription Machinery: A Review on the Mycobacterial RNA Polymerase and Drug Discovery Efforts. Stephanie F, Tambunan USF, Siahaan TJ. Life (Basel) 12 1774 (2022)
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Articles citing this publication (56)

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