The antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis.
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.
Department of Biochemistry, Stellenbosch University, Stellenbosch 7600, South Africa.
Renier
R
van der Westhuyzen
Justin C
JC
Hammons
Jordan L
JL
Meier
Samira
S
Dahesh
Wessel J A
WJ
Moolman
Stephen C
SC
Pelly
Victor
V
Nizet
Michael D
MD
Burkart
Erick
E
Strauss
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology*; D003065:Coenzyme A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000963:Antimetabolites; C449028:CJ-15,801; D010205:Pantothenic Acid; D003065:Coenzyme A