The increasing bacterial resistance to currently available antibiotics has created an urgent need for discovery of novel effective antibacterial agents. Among the other strategies, a promising approach is the discovery of new non-�-lactam antibiotics. The targets of these antibiotics are the penicillin-binding proteins (PBPs) or DD-peptidases. Penicillin-binding proteins are important bacterial enzymes, which catalyze the final peptide cross-linking step in peptidoglycan synthesis.  Directed by a computational fragment-based docking procedure, carried out on Escherichia coli PBP5, we have designed and synthesized a series of 4-quinolones derivatives as potential inhibitors of high molecular mass PBPs. We describe their binding to the PBPs by measuring dissociation constants (Ki) of these molecules from their PBP complexes in a competition with the irreversible reaction of the fluorescent penicillin Bocillin FL with membrane-bound PBPs of E. coli and B. subtilis. This research has shown that small suitably functionalized 2-hydroxyalkyl-4-quinolones are quite striking inhibitors of the high molecular mass PBPs of E. coli and B. subtilis, e.g. for E. coli PBP4, Ki values are ranging from 3 to 50 mM.

Fragment-based design, synthesis, and evaluation of a new class of effective non-�-lactam inhibitors of high molecular mass penicillin-binding proteins

247th National Meeting (2014)

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