| Literature DB >> 30705156 |
Elaine Ballinger1, John Mosior2, Travis Hartman3, Kristin Burns-Huang1, Ben Gold1, Roxanne Morris3, Laurent Goullieux4, Isabelle Blanc4, Julien Vaubourgeix1, Sophie Lagrange4, Laurent Fraisse4, Stéphanie Sans4, Cedric Couturier4, Eric Bacqué4, Kyu Rhee3, Sarah M Scarry5, Jeffrey Aubé5, Guangbin Yang6, Ouathek Ouerfelli6, Dirk Schnappinger1, Thomas R Ioerger1, Curtis A Engelhart1, Jennifer A McConnell1, Kathrine McAulay1, Allison Fay7, Christine Roubert4, James Sacchettini8, Carl Nathan9.
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.Entities:
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Year: 2019 PMID： 30705156 PMCID： PMC6613350 DOI： 10.1126/science.aau8959
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728