Vitamin imposters: Hijacking the biosynthesis of coenzyme A for antimicrobial drug development

Abstract

Humankind's struggle to find cures for infectious diseases is as old as humanity itself. During the last century, we have probably made the greatest advance in our battle against these diseases: the discovery of antibiotics. Importantly, the first antimicrobial agents introduced for clinical use in 1937, the sulfonamide drugs, act by hijacking the disease-causing organism's biosynthetic pathway for making folic acid, a vitamin that is required in the synthesis of DNA and RNA. Since then, many other antibiotics with diverse mechanisms of action have been discovered, and, by the early 1960s, it seemed as if any infection could be treated successfully with a course of antibiotics. However, since the first introduction of these drugs, we have also started to suffer our greatest defeat: bacterial strains that show resistance against nearly every antibiotic were often isolated within a few years of their first clinical use. We have been forced back to the drawing board to come up with new antimicrobials, and this has led us to revisit the antimetabolite inhibition strategy used by the sulfonamide drugs. This article discusses the recent advances that have made in discovering compounds that interfere with the biosynthesis of the essential metabolic cofactor coenzyme A (CoA) from pantothenate (vitamin B5).