Bacterial thiol- and metal-dependent enzymes

Bacterial thiol- and metal-dependent enzymes represent a broad class of catalytic proteins essential for bacterial survival, pathogenesis, and antibiotic resistance. Thiol-dependent enzymes, such as sortases and various cysteine proteases, utilize a conserved cysteine residue for their catalytic mechanism, often involved in cell wall assembly or the processing of virulence factors (Mazmanian et al., 1999, Science). Metal-dependent enzymes, or metalloenzymes, utilize divalent cations like zinc or iron to catalyze essential reactions, including protein maturation by peptide deformylases and the hydrolysis of antibiotics by metallo-beta-lactamases (Bush & Bradford, 2016, Cold Spring Harb Perspect Med). These enzymes are critical targets for drug discovery because they are often essential for bacterial viability or contribute significantly to multi-drug resistance phenotypes (Giglione et al., 2000, EMBO J). Inhibitors of these enzymes typically function by chelating the essential metal cofactor or reacting with the active-site thiol group, thereby halting bacterial metabolism or restoring antibiotic sensitivity (Fast & Sutton, 2013, Biochim Biophys Acta). However, achieving selectivity over human orthologs, such as matrix metalloproteinases or human cysteine proteases, remains a primary challenge in the clinical development of these inhibitors (McGowan et al., 2010, Chem Biol).

Other names

Bacterial metalloenzymesBacterial cysteine-dependent enzymesBacterial proteases and metabolic enzymes

Inhibition of enzymatic activity through metal ion chelation, covalent modification of active-site cysteine residues, or competitive binding to the active site.