The antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis

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dc.contributor.authorVan Der Westhuyzen R.
dc.contributor.authorHammons J.C.
dc.contributor.authorMeier J.L.
dc.contributor.authorDahesh S.
dc.contributor.authorMoolman W.J.A.
dc.contributor.authorPelly S.C.
dc.contributor.authorNizet V.
dc.contributor.authorBurkart M.D.
dc.contributor.authorStrauss E.
dc.date.accessioned2012-06-13T08:43:06Z
dc.date.available2012-06-13T08:43:06Z
dc.date.issued2012
dc.description.abstractThe natural product CJ-15,801 is an inhibitor of Staphylococcus aureus, but not other bacteria. Its close structural resemblance to pantothenic acid, the vitamin precursor of coenzyme A (CoA), and its Michael acceptor moiety suggest that it irreversibly inhibits an enzyme involved in CoA biosynthesis or utilization. However, its mode of action and the basis for its specificity have not been elucidated to date. We demonstrate that CJ-15,801 is transformed by the uniquely selective S. aureus pantothenate kinase, the first CoA biosynthetic enzyme, into a substrate for the next enzyme, phosphopantothenoylcysteine synthetase, which is inhibited through formation of a tight-binding structural mimic of its native reaction intermediate. These findings reveal CJ-15,801 as a vitamin biosynthetic pathway antimetabolite with a mechanism similar to that of the sulfonamide antibiotics and highlight CoA biosynthesis as a viable antimicrobial drug target. © 2012 Elsevier Ltd All rights reserved.
dc.identifier.citationChemistry and Biology
dc.identifier.citation19
dc.identifier.citation5
dc.identifier.citation559
dc.identifier.citation571
dc.identifier.issn10745521
dc.identifier.otherdoi:10.1016/j.chembiol.2012.03.013
dc.identifier.urihttp://hdl.handle.net/10019.1/21407
dc.titleThe antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis
dc.typeArticle
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