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[摘要]：We 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 angstrom) 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. |
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