Novel PPCS Inhibitors to Prevent CoA Biosynthesis in Drug-Resistant Pathogens
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The emergence of drug-resistant pathogens represents a major threat to human health. Growing attrition of effective drugs due to the development of resistant strains highlights a dire need for next generation antibiotics with novel mechanisms of action. In recent years, the coenzyme A (CoA) pathway has garnered significant attention. CoA is an essential cofactor involved in myriad cellular processes ranging from energy production to cell structure development. A universal CoA biosynthetic pathway exists in all prokaryotic and eukaryotic species, consisting of five enzymatic steps, termed CoaA-CoaE. In prokaryotes, the second and third steps occur within a bifunctional protein known as CoaBC. Although the enzymatic steps are conserved, key differences between the bacterial and human pathways enable the development of a selective inhibitor. Distinctive features of the binding pocket of CoaB, also known as phosphopantothenoylcysteine synthetase, present an opportunity for designing compounds that will preferentially inhibit CoA biosynthesis in prokaryotes, exhibiting a bactericidal effect. In this work, we describe the design and synthesis of a series of novel compounds targeting the inhibition of the bacterial PPCS activity. Compound design was based on the structure of the bacterial PPCS substrate, 4’-phosphopantothenoyl-cytidine monophosphate (P-Pan-CMP). Three subseries of compounds were designed, one developed for evaluation directly against CoaBC, and the other two developed with the goal of obtaining cellular inhibition. Several analogs have demonstrated promising results in terms of activity against selected pathogens. The synthesis and biological evaluation are presented in this dissertation.
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