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 β-alanine and pantoate, which has shown susceptibility to inhibition by analogs of its molecular constituents. Accordingly, analogs of β-alanine are gaining inquiry as potential antimicrobial chemotherapeutics.
Methods: We synthesized and evaluated 35 derivatives of β-alanine, substituted at the α, β, 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 µM/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.
Keywords: Antibacterial activity; Antimicrobial targets; Pantothenate; Pantothenate synthetase; β-Alanine.
© 2019 S. Karger AG, Basel.