Impact of Pyridyl Moieties on the Inhibitory Properties of Prominent Acyclic Metal Chelators Against Metallo-β-Lactamase-Producing Enterobacteriaceae: Investigating the Molecular Basis of Acyclic Metal Chelators' Activity

Abstract

Carbapenem-resistant Enterobacteriaceae (CREs)-mediated infections remain a huge public health concern. CREs produce enzymes such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Hence, developing efficient molecules capable of inhibiting these enzymes remains a way forward to overcoming this phenomenon. In this study, we demonstrate that pyridyl moieties favor the inhibitory activity of cyclic metal-chelating agents through in vitro screening, molecular modeling, and docking assays. Di-(2-picolyl) amine and tris-(2-picolyl) amine exhibited great efficacy against different types of MBLs and strong binding affinity for NDM-1, whereas 2-picolyl amine did not show activity at a concentration of 64 mg/L in combination with meropenem; it further showed the lowest binding affinity from computational molecular analysis, commensurating with the in vitro screening assays. The findings revealed that the pyridyl group plays a vital role in the inhibitory activity of the tested molecules against CREs and should be exploited as potential MBL inhibitors.