Novel Approaches Towards Inhibition of Bacterial CoA Biosynthesis
Open AccessThe ongoing emergence and spread of multidrug-resistant pathogens highlights the urgent need to develop next-generation antibacterial agents. Coenzyme A (CoA) is an essential cofactor in all living organisms due to its fundamental role in metabolism. A recent study investigating the effect that depletion of the pantothenic acid (Pan) and CoA biosynthetic enzymes has on bacterial cell viability provides convincing genetic validation of CoaBC as a bactericidal drug target. This leads to the hypothesis that inhibitors of CoaBC will disrupt CoA biosynthesis and kill bacterial cells. CoaBC is a bifunctional protein that harbors the enzymatic activities of both phosphopantothenoylcysteine synthetase (PPCS) and phosphopantothenoylcysteine decarboxylase (PPCDC), the second and third enzymes of the CoA biosynthetic pathway.In this work, we report the design and synthesis of a structurally diverse range of novel inhibitors targeting the PPCS activity of bacterial CoaBC. These compounds are Pan analogs, the natural substrate of PanK catalyzed phosphorylation in the first step of CoA biosynthesis. A metabolic activation strategy was employed to generate cell-permeable inhibitors that act as substrates for the organism’s native PanK enzyme, undergoing phosphorylation and subsequent cytidylation to form the active PPCS inhibitor in situ. In a parallel strategy, a series of phosphorylated prodrugs have been prepared, bypassing metabolic activation. A third series of compounds were designed to deliver the intact inhibitor. The synthesis and biological evaluation of these compounds is presented in this dissertation.
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