The antibiotic activity of N-pentylpantothenamide results from its conversion to ethyldethia-coenzyme A, a coenzyme A antimetabolite

Abstract

Pantothenic acid (vitamin B5) 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 μ. 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-pentylpantohenamide does not inhibit the CoA biosynthetic enymes 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 biosynhesis 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 ethyldehia-CoA, which may act as an inhibitor of CoA. and utilizing enzymes.