Antibiotic evaluation and in vivo analysis of alkynyl Coenzyme A antimetabolites in Escherichia coli

A panel of pantetheine analogues was synthesized and the mechanism of their differential activity against Escherichia coli was probed with a series of kinetic and in vivo assays. The results have implications on the purported mode of action of this class of antibiotics. Pantothenamides have been the subject of much study as potential inhibitors of CoA and carrier protein dependent biosynthetic pathways. Based on an initial observation of growth inhibition in Escherichia coli by 3, we have synthesized a small panel of pantetheine analogues and re-examined the inhibitory properties of this class of antibiotics with an emphasis on understanding the ability of these compounds to act as substrates of native CoA and carrier protein utilizing biosynthetic pathways. Our findings suggest that a secondary structure–activity relationship is an important factor in the antibiotic activity of these compounds.