Metalloenzyme mimicry and modulation strategies to conquer antimicrobial resistance: Metal-ligand coordination perspectives

The incessant resistivity of pathogenic microbes to antibiotics continuously constitutes a major threat to human wellness, thus, searching for effective therapeutic approaches remains essential. Metalloenzymes such as erythromycin esterases, β-lactamases, N-acetyltransferases, staphylopine dehydrogenases significantly confer antibiotic resistance and cell defence in superbugs including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Helicobacter pylori and Staphylococcus aureus. These occur through various pathomechanisms including modulations of intracellular targets, hydrolytic cleavage and cellular metabolism of antibiotics, redox catalysis, and oftentimes via the attraction/donation of electrons during labile coordination to substrates. Several inhibitors of these therapeutic pathways have been reported including metal chelators and chelates. However, the overview of these innovative anti-resistance strategies remains sparse. We hereby present a comprehensive review of the coordination chemistry of metalloenzymes in the resistance development and modulatory potentials of metal-chelating and metal complex inhibitors for catalytic deactivation. These include the removal/replacement of biotic metal ions and/or chelating agents to induce loss of resistivity and specificity, and suppression of catalytic activities as potential therapeutic strategies. Selectively, imipenem, meropenem, hesperidin, aspergillomarasmine A, picolinic, rosmarinic and salvianolic acids represent potent metal-chelating inhibitors of the metallo-β-lactamases, ligands B67-B78 as promising candidates against ureases, while B79-B83 effectively suppressed catalysis of polyphenol oxidases. Some metal chelates also demonstrated potentials to mitigate the defence/resistivity of the metalloenzymes hypothetically through the acquisition of abiotic metals ions, accumulation of antimicrobial ligands and blockage of active metalloenzyme sites. This review represents a model for innovative therapeutic strategies to overcome antimicrobial resistance through metalloenzyme mimicry and modulation for further studies.