Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C ß-Lactamase from Escherichia coli.

Resistance to ß-lactam antibacterials, importantly via production of ß-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) ß-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C ß­lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied ß-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D ß­lactamases, our data support the proposal that bicyclic boronates are broad-spectrum ß­lactamase inhibitors that work by mimicking a high energy 'tetrahedral' intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful ß-lactamase inhibition.

Broad Spectrum ß-Lactamase Inhibition by a Thioether Substituted Bicyclic Boronate.

ß-Lactamases comprise the most widely used mode of resistance to ß-lactam antibiotics. Cyclic boronates have shown promise as a new class of ß-lactamase inhibitor, with pioneering potential to potently inhibit both metallo- and serine-ß-lactamases. We report studies concerning a bicyclic boronate ester with a thioether rather than the more typical ß-lactam antibiotic "C-6/C-7" acylamino type side chain, which is present in the penicillin/cephalosporin antibiotics. The thioether bicyclic boronate ester was tested for activity against representative serine- and metallo-ß-lactamases. The results support the broad inhibition potential of bicyclic boronate based inhibitors with different side chains, including against metallo-ß-lactamases from B1, B2, and B3 subclasses. Combined with previous crystallographic studies, analysis of a crystal structure of the thioether inhibitor with the clinically relevant VIM-2 metallo-ß-lactamase implies that further SAR work will expand the already broad scope of ß-lactamase inhibition by bicyclic boronates.