Cyclic Boronates Inhibit All Classes of beta-Lactamases

摘要

Lactamase- mediated resistance is a growing threat to the continued use of beta- lactam antibiotics. The use of the beta-lactam-based serine-beta-lactamase ( SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-beta lactam inhibitor avibactam has extended the utility of beta-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-beta-lactamases ( MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-beta-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of "dual-action" inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine-and metallo-beta-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of beta-lactamase, including the class A extended spectrum beta-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of beta-lactams against Gram-negative clinical isolates expressing a variety of beta-lactamases. Comparison of a crystal structure of a CTX-M-15: cyclic boronate complex with structures of cyclic boronates complexed with other beta-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine-and metallo-beta-lactamase catalysis.