The incessant resistivity of pathogenic microbes to antibiotics continuously constitutes a major threat to human healthcare, thereby making search for alternative approaches imperative. Metalloenzymes significantly confer antibiotic resistance and cell defence in several bacterial strains including <i>Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus </i>and<i> Staphylococcus aureus</i> through various pathomechanisms including modulations of intracellular targets, cellular metabolism of antibiotics and redox catalysis. Oftentimes, the mechanisms involve the attraction/donation of electrons during labile coordination to substrates. Thus, the analysis of the enzymatic implications of these biomacromolecules and their mutants in resistance development could pave ways for strategic drug designs to overcome resistance challenges. We hereby present a succinct analysis of some metal chelators and chelates with mimicry potentials to deactivate such metalloenzymes through structural modifications to induce loss of resistivity and specificity, implicating potential therapeutic strategy. The highlighted inhibitors could effectively mitigate defence/resistivity of the pathogenic microorganisms through mechanisms hypothetically as sequestration and displacement of the biotic metal cofactors of the enzymes, coordination of metal cofactors to antimicrobial ligands, increment of antimicrobial moieties and blockage of active sites by the complexes. This review represents a model for innovative therapeutic designs amenable for overcoming microbial resistance through metalloenzyme mimicry and modulation upon further studies.

Metalloenzyme mimicry as potential therapeutic approach for overcoming antimicrobial resistance: Metal-ligand coordination perspectives

ACS Fall 2021

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