Design, synthesis, crystal structures and antimicrobial activity of sulfonamide boronic acids as beta-lactamase inhibitors

β-Lactamase-mediated resistance to β-lactam antibiotics threatens our antibiotic armamentarium. We investigated a new series of sulfonamide boronic acids against AmpC, a class C beta-lactamase that confers extended spectrum resistance to beta-lactams worldwide. Previously, we had explored transition-state analog carboxamide boronic acids and another, unrelated series of non-covalent inhibitors bearing sulfonamide side chains. Merging these two series resulted in boronic acids that differed in the replacement of the canonical carboxamide, which was inserted to mimic the amide in C6/C7 of peniccilins and cephalosporins, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct SAR from the carboxamides, with Ki values 23 times better for small analogs and Ki values 10 to 20 times worse than the carboxamide congener for larger molecules. X-ray crystal structures of three of the new sulfonamides explain this dramatically changed SAR. The most potent of these beta-lactamase inhibitors were tested in cell culture and showed good ability to reverse beta-lactamase mediated resistance to third generation cephalosporins.