Characterization of a novel inhibitor for the New Delhi metallo--lactamase-4: Implications for drug design and combating bacterial drug resistance

The bacterial metallo-11-lactamases (MBLs) catalyze the inactivation of 11-lactam antibiotics. Identifying novel pharmacophores remains crucial for the clinical development of additional MBL inhibitors. Previously, 1-hydroxypyridine2(1H)-thione-6-carboxylic acid, hereafter referred to as 1,2HPT-6-COOH, was reported as a low cytotoxic nanomolar 11-lactamase inhibitor of Verona-integron-encoded metallo-11lactamase 2, capable of rescuing 11-lactam antibiotic activity. In this study, we explore its exact mechanism of inhibition and the extent of its activity through structural characterization of its binding to New Delhi metallo-11-lactamase 4 (NDM-4) and its inhibitory activity against both NDM-1 and NDM-4. Of all the structure-validated MBL inhibitors available, 1,2-HPT-6COOH is the first discovered compound capable of forming an octahedral coordination sphere with Zn2 of the binuclear metal center. This unexpected mechanism of action provides important insight for the further optimization of 1,2-HPT-6COOH and the identification of additional pharmacophores for MBL inhibition.