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Title: A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase

Abstract

New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes—primarily those involved in macromolecular synthesis—are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB a–b-subunit interface and affects multiple steps in the enzyme’s overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Broad Institute; Pershing Square Foundation (PSF); Bill and Melinda Gates Foundation; National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); USDOE Office of Science - Office of Biological and Environmental Research
OSTI Identifier:
1389281
DOE Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 13; Journal Issue: 9; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Wellington, Samantha, Nag, Partha P., Michalska, Karolina, Johnston, Stephen E., Jedrzejczak, Robert P., Kaushik, Virendar K., Clatworthy, Anne E., Siddiqi, Noman, McCarren, Patrick, Bajrami, Besnik, Maltseva, Natalia I., Combs, Senya, Fisher, Stewart L., Joachimiak, Andrzej, Schreiber, Stuart L., and Hung, Deborah T. A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. United States: N. p., 2017. Web. doi:10.1038/nchembio.2420.
Wellington, Samantha, Nag, Partha P., Michalska, Karolina, Johnston, Stephen E., Jedrzejczak, Robert P., Kaushik, Virendar K., Clatworthy, Anne E., Siddiqi, Noman, McCarren, Patrick, Bajrami, Besnik, Maltseva, Natalia I., Combs, Senya, Fisher, Stewart L., Joachimiak, Andrzej, Schreiber, Stuart L., & Hung, Deborah T. A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. United States. doi:10.1038/nchembio.2420.
Wellington, Samantha, Nag, Partha P., Michalska, Karolina, Johnston, Stephen E., Jedrzejczak, Robert P., Kaushik, Virendar K., Clatworthy, Anne E., Siddiqi, Noman, McCarren, Patrick, Bajrami, Besnik, Maltseva, Natalia I., Combs, Senya, Fisher, Stewart L., Joachimiak, Andrzej, Schreiber, Stuart L., and Hung, Deborah T. Mon . "A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase". United States. doi:10.1038/nchembio.2420.
@article{osti_1389281,
title = {A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase},
author = {Wellington, Samantha and Nag, Partha P. and Michalska, Karolina and Johnston, Stephen E. and Jedrzejczak, Robert P. and Kaushik, Virendar K. and Clatworthy, Anne E. and Siddiqi, Noman and McCarren, Patrick and Bajrami, Besnik and Maltseva, Natalia I. and Combs, Senya and Fisher, Stewart L. and Joachimiak, Andrzej and Schreiber, Stuart L. and Hung, Deborah T.},
abstractNote = {New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes—primarily those involved in macromolecular synthesis—are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB a–b-subunit interface and affects multiple steps in the enzyme’s overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.},
doi = {10.1038/nchembio.2420},
journal = {Nature Chemical Biology},
issn = {1552-4450},
number = 9,
volume = 13,
place = {United States},
year = {2017},
month = {7}
}

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