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

doi:10.1016/j.molcel.2017.03.001

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

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118 Scopus citations

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 language	English (US)
Pages (from-to)	169-179.e8
Journal	Molecular cell
Volume	66
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2017.03.001
State	Published - Apr 20 2017

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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

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10.1016/j.molcel.2017.03.001

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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

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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 {\AA} 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.",

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",

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

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doi = "10.1016/j.molcel.2017.03.001",

language = "English (US)",

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T1 - Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

AU - Lin, Wei

AU - Mandal, Soma

AU - Degen, David

AU - Liu, Yu

AU - Ebright, Yon W.

AU - Li, Shengjian

AU - Feng, Yu

AU - Zhang, Yu

AU - Mandal, Sukhendu

AU - Jiang, Yi

AU - Liu, Shuang

AU - Gigliotti, Matthew

AU - Talaue, Meliza

AU - Connell, Nancy

AU - Das, Kalyan

AU - Arnold, Eddy

AU - Ebright, Richard H.

PY - 2017/4/20

Y1 - 2017/4/20

N2 - 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.

AB - 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.

KW - AAPs

KW - D-AAP1

KW - Nα-aroyl-N-aryl-phenylalaninamides

KW - RNA polymerase

KW - RNA polymerase inhibitors

KW - RNA polymerase-promoter initial transcribing complex

KW - RNA polymerase-promoter open complex

KW - antituberculosis agents

KW - promoter

KW - rifampin

KW - sigma factor

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C2 - 28392175

AN - SCOPUS:85017151176

SN - 1097-2765

VL - 66

SP - 169-179.e8

JO - Molecular cell

JF - Molecular cell

IS - 2

ER -

Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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