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

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

doi:10.1126/science.aau8959

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

Journal Article · Fri Feb 01 00:00:00 EST 2019 · Science

DOI:https://doi.org/10.1126/science.aau8959· OSTI ID:1504971

;

; Burns-Huang, Kristin;

;

; Goullieux, Laurent; Blanc, Isabelle;

; Lagrange, Sophie; Fraisse, Laurent;

;

; Rhee, Kyu;

;

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of Allergy and Infectious Diseases (NIAID); Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine; Welch Foundation; TB Structural Genomics; Bill and Melinda Gates Foundation; National Cancer Institute (NCI); William Randolph Hearst Foundation

Grant/Contract Number:: AC02-06CH11357; U19AI-111143; A-0015; P01AI095208; P30 CA008748

OSTI ID:: 1504971

Journal Information:: Science, Vol. 363, Issue 6426; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 37 works

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