Design and Synthesis of Bimetallic Cu(II) Compounds as Potent Antibacterial and Antibiofilm Agents with Metallo- β -Lactamase Inhibitory Activityagainst Multidrug Resistant Pseudomonas aeruginosa.

Abstract

In this research, a novel class of biologically active bimetallic Cu(II) compounds have been discovered as cutting-edge antibiofilm agents with metallo-β-lactamase (MBL) inhibitory activity against the clinically isolated multidrug resistant (MDR) gram-negative bacterium, Pseudomonas aeruginosa (Pa-CI-1). Thus, the 2,6-bis[N-{N-(carboxymethyl)-N-(pyridylmethyl)amine}methyl]-4-methylphenol (H3L)-incorporated three bimetallic Cu(II) compounds, [Cu2L(H2O)(Cl)]∙H2O (1), [Cu2L(H2O)(NO3)]∙H2O (2) and [Cu2L(H2O)(CH3CO2)]∙H2O (3) have been strategically designed and synthesized with unsymmetrical coordination arrangement that synergistically modifies the electronic environment of Cu centres for the enhancement of antibacterial and antibiofilm activity. The standard nitrocefin assay disclosed that 1-3 significantly inhibited the activity of MBLs produced by Pa-CI-1 at their 1/2 MIC doses. Molecular docking study revealed an excellent propensity of these Cu compounds for binding with different MBL-producing proteins. All three Cu(II) compounds displayed significantly high antibacterial and antibiofilm activity as established by multiple bioassays, including ex-vivo applicability studies. They showed an exceptional combinatorial activity when examined with commercially accessible five different β-lactam-based antibiotics such as amoxicillin (AMX), chloramphenicol (CHL), cefotaxime (CTX), ceftriaxone (CTR) and Cefoxitin (CX) against Pa-CI-1. Our study disclosed that 1-3 could be the emergent drug leads and attract great attention to the inorganic, material and biological chemists, combating antimicrobial resistance.