The antibiotic activity of N-pentylpantothenamide results from its conversion to ethyldethia-coenzyme a, a coenzyme a antimetabolite.
Pantothenic acid (vitamin B(5)) is the natural precursor of coenzyme A (CoA), an essential cofactor in all organisms. The pantothenic acid antimetabolite N-pentylpantothenamide inhibits the growth of Escherichia coli with a minimum inhibitory concentration of 2 microm. In this study, we examine the mechanism of this inhibition. Using the last five enzymes of the CoA biosynthetic pathway in E. coli we demonstrate that N-pentylpantothenamide does not inhibit the CoA biosynthetic enzymes but instead acts as an alternative substrate, forming the CoA analog ethyldethia-CoA. We show that N-pentylpantothenamide is converted to ethyldethia-CoA 10.5 times faster than CoA is biosynthesized from pantothenic acid, demonstrating that ethyldethia-CoA biosynthesis can effectively compete with CoA biosynthesis in the cell. We conclude that the mechanism of toxicity of N-pentylpantothenamide is most likely due to its biosynthetic conversion to the CoA analog ethyldethia-CoA, which may act as an inhibitor of CoA- and acetyl-CoA-utilizing enzymes.
Strauss
Erick
E
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York, 14853, USA.
Begley
Tadhg P
TP
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D003065:Coenzyme A / Q000378:metabolism*; D017931:DNA Primers; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D010205:Pantothenic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D017931:DNA Primers; C470569:N-pentylpantothenamide; D010205:Pantothenic Acid; D003065:Coenzyme A