Microbial metal-dependent enzymes and membranes

Microbial metal-dependent enzymes and membranes represent a broad category of biological structures and proteins essential for the survival and virulence of pathogenic microorganisms. Metal-dependent enzymes, or metalloenzymes, utilize metal ions such as zinc, iron, or manganese as essential cofactors for catalytic activities, including the hydrolysis of beta-lactam antibiotics by metallo-beta-lactamases and the removal of N-terminal formyl groups by peptide deformylases (Bush, 1998; Giglione et al., 2000). Microbial membranes, including the cytoplasmic membrane and the outer membrane of Gram-negative bacteria, maintain cellular integrity and regulate ion homeostasis (Straus & Hancock, 2006). Drugs targeting these entities include membrane-disrupting lipopeptides like daptomycin and polymyxins, as well as experimental inhibitors that sequester metal ions or bind to the active sites of metalloenzymes (Velkov et al., 2010; King et al., 2014). A major challenge in targeting these components is achieving sufficient selectivity to avoid cross-reactivity with human membranes or host metalloenzymes, which can result in significant toxicities such as nephrotoxicity or neurotoxicity (Falagas & Kasiakou, 2006). This target group is particularly relevant in the context of multi-drug resistant (MDR) infections where traditional antibiotic targets have been bypassed.

Other names

Microbial metalloenzymesBacterial cell membranesFungal cell membranesMetal-dependent microbial proteinsBacterial cell envelope

Drugs targeting this group act either by physically disrupting the microbial lipid bilayer, leading to cytoplasmic leakage and cell death, or by inhibiting metal-dependent enzymes through the chelation of essential metal cofactors or competitive inhibition of the active site.