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Title: Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition

Abstract

Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIAID
OSTI Identifier:
1504971
Resource Type:
Journal Article
Journal Name:
Science
Additional Journal Information:
Journal Volume: 363; Journal Issue: 6426; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Ballinger, Elaine, Mosior, John, Hartman, Travis, Burns-Huang, Kristin, Gold, Ben, Morris, Roxanne, Goullieux, Laurent, Blanc, Isabelle, Vaubourgeix, Julien, Lagrange, Sophie, Fraisse, Laurent, Sans, Stéphanie, Couturier, Cedric, Bacqué, Eric, Rhee, Kyu, Scarry, Sarah M., Aubé, Jeffrey, Yang, Guangbin, Ouerfelli, Ouathek, Schnappinger, Dirk, Ioerger, Thomas R., Engelhart, Curtis A., McConnell, Jennifer A., McAulay, Kathrine, Fay, Allison, Roubert, Christine, Sacchettini, James, and Nathan, Carl. Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition. United States: N. p., 2019. Web. doi:10.1126/science.aau8959.
Ballinger, Elaine, Mosior, John, Hartman, Travis, Burns-Huang, Kristin, Gold, Ben, Morris, Roxanne, Goullieux, Laurent, Blanc, Isabelle, Vaubourgeix, Julien, Lagrange, Sophie, Fraisse, Laurent, Sans, Stéphanie, Couturier, Cedric, Bacqué, Eric, Rhee, Kyu, Scarry, Sarah M., Aubé, Jeffrey, Yang, Guangbin, Ouerfelli, Ouathek, Schnappinger, Dirk, Ioerger, Thomas R., Engelhart, Curtis A., McConnell, Jennifer A., McAulay, Kathrine, Fay, Allison, Roubert, Christine, Sacchettini, James, & Nathan, Carl. Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition. United States. doi:10.1126/science.aau8959.
Ballinger, Elaine, Mosior, John, Hartman, Travis, Burns-Huang, Kristin, Gold, Ben, Morris, Roxanne, Goullieux, Laurent, Blanc, Isabelle, Vaubourgeix, Julien, Lagrange, Sophie, Fraisse, Laurent, Sans, Stéphanie, Couturier, Cedric, Bacqué, Eric, Rhee, Kyu, Scarry, Sarah M., Aubé, Jeffrey, Yang, Guangbin, Ouerfelli, Ouathek, Schnappinger, Dirk, Ioerger, Thomas R., Engelhart, Curtis A., McConnell, Jennifer A., McAulay, Kathrine, Fay, Allison, Roubert, Christine, Sacchettini, James, and Nathan, Carl. Thu . "Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition". United States. doi:10.1126/science.aau8959.
@article{osti_1504971,
title = {Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition},
author = {Ballinger, Elaine and Mosior, John and Hartman, Travis and Burns-Huang, Kristin and Gold, Ben and Morris, Roxanne and Goullieux, Laurent and Blanc, Isabelle and Vaubourgeix, Julien and Lagrange, Sophie and Fraisse, Laurent and Sans, Stéphanie and Couturier, Cedric and Bacqué, Eric and Rhee, Kyu and Scarry, Sarah M. and Aubé, Jeffrey and Yang, Guangbin and Ouerfelli, Ouathek and Schnappinger, Dirk and Ioerger, Thomas R. and Engelhart, Curtis A. and McConnell, Jennifer A. and McAulay, Kathrine and Fay, Allison and Roubert, Christine and Sacchettini, James and Nathan, Carl},
abstractNote = {Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.},
doi = {10.1126/science.aau8959},
journal = {Science},
issn = {0036-8075},
number = 6426,
volume = 363,
place = {United States},
year = {2019},
month = {1}
}

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