Loyola University Chicago, Department of Chemistry, Chicago, IL 60626
The emergence of pathogenic bacterial strains that are resistant to currently available antibiotics emphasizes the need for development of new classes of antibiotics which target enzymes in unexplored bacterial biosynthetic pathways.
DapE is a member of the bacterial meso-diaminopimelate/lysine biosynthetic pathway. It is a small, dimeric enzyme which is essential for bacterial cell growth and proliferation and is the only source of lysine in bacteria. Inhibitors of this biosynthesis have proven to be very potent antibiotics, evidence that interfering with cell wall synthesis can have deleterious effects on bacterial cell survival. A targeted screen of inhibitors of the DapE enzyme has uncovered several promosing lead structures, including several thiol structures. Several mercaptobenzoic acid derivatives were synthesized as potential dapE enzyme inhibitors. Aryl-linked mercapto benzoic acid amides comprise one focus of our recent medicinal chemistry research. In situ acetylation protects the thiol of the mercaptobenzoic acids enabling acid chloride or carbodiimide coupling with amino acids and related derivatives followed by deprotection affords targets for testing versus DapE.
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