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- Title
Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy.
- Authors
Liyanage, S. Imindu; Gupta, Mayuri; Wu, Fan; Taylor, Marcy; Carter, Michael D.; Weaver, Donald F.
- Abstract
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.
- Subjects
COENZYME A; MICROBIAL virulence; PSEUDOMONAS aeruginosa; STAPHYLOCOCCUS aureus; AMINES
- Publication
Chemotherapy (0009-3157), 2019, Vol 64, Issue 1, p22
- ISSN
0009-3157
- Publication type
Article
- DOI
10.1159/000499899