The Calcium-Dependent Cyclic Lipopeptide Antibiotic Superfamily-Structural Diversity and Biological Activity.

The rapid emergence of multidrug-resistant (MDR) bacteria threatens the effectiveness of existing antibiotics and has created an urgent need for agents with novel mechanisms of action. Calcium-dependent antibiotics (CDAs), a structurally diverse group of nonribosomal cyclic lipopeptides, have gained attention for their potent activity against Gram-positive pathogens, including strains resistant to conventional therapies. Their hallmark feature is Ca2+-mediated activation: the calcium ion binding to the lipopeptide enables selective interactions with bacterial lipids or cell-wall precursors. This review examines the relationship between CDA structure, Ca2+ coordination, mechanistic diversity, and biological activity. Together, these features position CDAs as promising templates for next-generation therapeutics to combat the escalating MDR crisis.