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Chem Biol. 2012 May 25;19(5):559-71. doi: 10.1016/j.chembiol.2012.03.013.

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

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1
Department of Biochemistry, Stellenbosch University, Stellenbosch 7600, South Africa.

Abstract

The 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.

PMID:
22633408
PMCID:
PMC3361698
DOI:
10.1016/j.chembiol.2012.03.013
[Indexed for MEDLINE]
Free PMC Article
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