The Antibiotic CJ-15,801 Is an Antimetabolite that Hijacks and Then Inhibits CoA Biosynthesis

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (373 K)Download as PowerPoint slideHighlights► CJ-15,801 is a natural product inhibitor of coenzyme A (CoA) biosynthesis ► Its unique selectivity is due to the gatekeeping action of pantothenate kinase ► The first two CoA biosynthetic enzymes convert it into a tight-binding inhibitor ► Pantothenamides (precursors of known CoA antimetabolites) increase its potency