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4-quinolones as noncovalent inhibitors of high molecular mass penicillin-binding proteins.


ABSTRACT: Penicillin-binding proteins (PBPs) are important bacterial enzymes that carry out the final steps of bacterial cell wall assembly. Their DD-transpeptidase activity accomplishes the essential peptide cross-linking step of the cell wall. To date, all attempts to discover effective inhibitors of PBPs, apart from ?-lactams, have not led to new antibiotics. Therefore, the need for new classes of efficient inhibitors of these enzymes remains. Guided by a computational fragment-based docking procedure, carried out on Escherichia coli PBP5, we have designed and synthesized a series of 4-quinolones as potential inhibitors of PBPs. We describe their binding to the PBPs of E. coli and Bacillus subtilis. Notably, these compounds bind quite tightly to the essential high molecular mass PBPs.

SUBMITTER: Shilabin AG 

PROVIDER: S-EPMC4025767 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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4-quinolones as noncovalent inhibitors of high molecular mass penicillin-binding proteins.

Shilabin Abbas G AG   Dzhekieva Liudmila L   Misra Pushpa P   Jayaram B B   Pratt R F RF  

ACS medicinal chemistry letters 20120604 7


Penicillin-binding proteins (PBPs) are important bacterial enzymes that carry out the final steps of bacterial cell wall assembly. Their DD-transpeptidase activity accomplishes the essential peptide cross-linking step of the cell wall. To date, all attempts to discover effective inhibitors of PBPs, apart from β-lactams, have not led to new antibiotics. Therefore, the need for new classes of efficient inhibitors of these enzymes remains. Guided by a computational fragment-based docking procedure,  ...[more]

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