Dinuclear Zinc(II) Complexes as Metallo-β-Lactamase Inhibitors with Antibiofilm Activity against MDR Gram-Negative Bacteria.

The alarming upsurge of multidrug-resistant (MDR) bacterial infection poses a serious burden to global health. The gradual restriction of advanced β-lactam-based antibiotic usage is mechanistically driven by bacterial metallo-β-lactamase (MBL) secretion, causing significant therapeutic failure and infection persistence. Furthermore, biofilm development has led to the disease scenario becoming more severe by restricting antibiotic penetration and immune responses. The present article describes a strategic design and development of dinuclear zinc(II) complex-based MBL inhibitors, coupled with antibacterial and antibiofilm activity against gram-negative MDR superbugs. Hence, a series of three dinuclear zinc(II) complexes, namely [Zn2L(Cl)(H2O)2]·4H2O (1), [Zn2L(NO3)(H2O)2]·4H2O (2) and [Zn2L(OAc)(H2O)2]·4H2O (3) were successfully constructed using the organic ligand, 2,6-bis[N-{N-(carboxymethyl)-N-(pyridylmethyl)amine}methyl]-4-methylphenol (H3L). Single crystal X-ray diffraction analysis revealed that the formation of complexes 1-3 was accomplished via the unsymmetrical metal-ligand coordination around the zinc centers, with five- and six-coordinate environments. The novelty of complexes 1-3 primarily lies in their effectiveness in antibacterial and antibiofilm properties, including MBL inhibitory application. Among these three dizinc complexes, 3 exhibited significant antibacterial activity against the clinical isolates of gram-negative MDR bacteria, such as Escherichia coli (Ec-CI-4), Acinetobacter baumannii (Ab-CI-2) and Klebsiella pneumonia (Kp-CI-5), with minimum inhibitory concentration (MIC) values of 250, 250 and 350 μg/mL, respectively. Again, complex 3 showed maximum biofilm reduction capability with 74.42, 77.45 and 69.37% for Ec-CI-4, Ab-CI-2 and Kp-CI-5, respectively. Our as-synthesized complex 3 also displayed MBL inhibitory activity as evidenced by nitrocefin analysis and in silico molecular docking study. Furthermore, the biofilm eradication nature of 3 was also found to be significant from the surfaces of urinary catheters and contact lenses, highlighting its future applicability potential. Therefore, complex 3 could emerge as an MBL inhibitor confronting MDR bacterial infections and medicinal implant-associated maladies as a significant therapeutic alternative over conventional antibacterial treatment regimens.