Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy

Background: Pantothenate, the fundamental precursor to coenzyme A, is required for optimal growth and virulence of microbial pathogens. It is synthesized by the enzyme-catalyzed condensation of beta-alanine and pantoate, which has shown susceptibility to inhibition by analogs of its molecular constituents. Accordingly, analogs of beta-alanine are gaining inquiry as potential antimicrobial chemotherapeutics. Methods: We synthesized and evaluated 35 derivatives of beta-alanine, substituted at the alpha, beta, amine, and carboxyl sites, derived from in silico, dynamic molecular modeling to be potential competitive inhibitors of pantothenate synthetase. Employing the Clinical Laboratory Standards M7-A6 broth microdilution method, we tested these for inhibition of growth in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Results: All compounds proved entirely ineffective in all species tested, with no inhibition of growth being observed up to 200 mu M/mL. Conclusions: Upon revision of the literature, we conclude that high enzyme selectivity or external salvage mechanisms may render this strategy futile against most bacteria. (C) 2019 S. Karger AG, Basel