Discovery of a novel covalent non-β-lactam inhibitor of the metallo-β-lactamase NDM-1

The inhibition of metallo-beta-lactamases (MBL) can prevent the hydrolysis of beta-lactam antibiotics and hence is a promising strategy for the treatment of antibiotic resistant infections. In this study, we present a novel reversible covalent inhibitor of the clinically relevant MBL New Delhi metallo-beta-lactamase 1 (NDM-1). Electrospray ionization-mass spectrometry (ESI-MS) and single site directed mutagenesis were used to show that the inhibitor forms a covalent bond with Lys224 in the active site of NDM-1. The inhibitor was further characterized using an enzyme inhibition assay, a surface plasmon resonance (SPR) based biosensor assay and covalent docking. The determined inhibition constant (K-I(*)) was 580 nM and the inhibition constant for the initial complex (K-I) was 76 mu M. To our knowledge, this inhibitor is the first example for a reversible covalent non-beta-lactam inhibitor targeting NDM-1 and a promising starting point for the design of potent covalent inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.