3o86
Crystal structure of AmpC beta-lactamase in complex with a sulfonamide boronic acid inhibitorCrystal structure of AmpC beta-lactamase in complex with a sulfonamide boronic acid inhibitor
Structural highlights
FunctionAMPC_ECOLI This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. Publication Abstract from PubMedWe investigated a series of sulfonamide boronic acids that resulted from the merging of two unrelated AmpC beta-lactamase inhibitor series. The new boronic acids differed in the replacement of the canonical carboxamide, found in all penicillin and cephalosporin antibiotics, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct structure-activity relationship from the previously explored carboxamides, high ligand efficiencies (up to 0.91), and K(i) values down to 25 nM and up to 23 times better for smaller analogues. Conversely, K(i) values were 10-20 times worse for larger molecules than in the carboxamide congener series. X-ray crystal structures (1.6-1.8 A) of AmpC with three of the new sulfonamides suggest that this altered structure-activity relationship results from the different geometry and polarity of the sulfonamide versus the carboxamide. The most potent inhibitor reversed beta-lactamase-mediated resistance to third generation cephalosporins, lowering their minimum inhibitory concentrations up to 32-fold in cell culture. Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as beta-Lactamase Inhibitors.,Eidam O, Romagnoli C, Caselli E, Babaoglu K, Pohlhaus DT, Karpiak J, Bonnet R, Shoichet BK, Prati F J Med Chem. 2010 Oct 14. PMID:20945905[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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