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

Elaine Ballinger | Zendy; John Mosior | Zendy; Travis Hartman | Zendy; Kristin Burns-Huang | Zendy; Ben Gold | Zendy; Roxanne Morris | Zendy; Laurent Goullieux | Zendy; Isabelle Blanc | Zendy; Julien Vaubourgeix | Zendy; Sophie Lagrange | Zendy; Laurent Fraisse | Zendy; Stéphanie Sans | Zendy; Cédric Couturier | Zendy; Eric Bacqué | Zendy; Kyu Y. Rhee | Zendy; Sarah M. Scarry | Zendy; Jeffrey Aubé | Zendy; Guangbin Yang | Zendy; Ouathek Ouerfelli | Zendy; Dirk Schnappinger | Zendy; Thomas R. Ioerger | Zendy; Curtis A. Engelhart | Zendy; Jennifer A. McConnell | Zendy; Kathrine McAulay | Zendy; Allison Fay | Zendy; Christine Roubert | Zendy; James C. Sacchettini | Zendy; Carl Nathan | Zendy

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

Author(s) -

Elaine Ballinger,

John Mosior,

Travis Hartman,

Kristin Burns-Huang,

Ben Gold,

Roxanne Morris,

Laurent Goullieux,

Isabelle Blanc,

Julien Vaubourgeix,

Sophie Lagrange,

Laurent Fraisse,

Stéphanie Sans,

Cédric Couturier,

Eric Bacqué,

Kyu Y. Rhee,

Sarah M. Scarry,

Jeffrey Aubé,

Guangbin Yang,

Ouathek Ouerfelli,

Dirk Schnappinger,

Thomas R. Ioerger,

Curtis A. Engelhart,

Jennifer A. McConnell,

Kathrine McAulay,

Allison Fay,

Christine Roubert,

James C. Sacchettini,

Carl Nathan

Publication year - 2019

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aau8959

Subject(s) - mycobacterium tuberculosis , enzyme , metabolism , microbiology and biotechnology , chemistry , cofactor , biochemistry , coenzyme a , mycobacterium , tuberculosis , biology , medicine , reductase , pathology

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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