Natural cyclic depsipeptides and their analogs as potential antimicrobial candidates: mechanistic insight.

Microorganisms such as bacteria, viruses, fungi, and parasites cause serious infections in humans. The misuse of antimicrobial treatments in humans, animals, and agriculture has led to the development of resistant pathogens that can survive and multiply even in the presence of antibiotics. The rise of antibiotic-resistant pathogens has caused significant loss of life and impacted social and economic conditions. Antimicrobial peptides exert antibacterial activity through multiple modes of action. Cyclic peptides are known for greater stability and bioavailability than linear peptides. Among them, cyclic depsipeptides represent a distinct subclass characterized by the presence of an ester bond in addition to peptide bonds. Because of the distinct molecular structure of cyclic depsipeptides, particularly their amino acid components, they demonstrate robust antimicrobial efficacy. Cyclic depsipeptides demonstrate antimicrobial efficacy by targeting various components of the cell wall, including lipid II, menaquinone, lipopolysaccharides, and the DNA polymerase β sliding clamp, as well as by inhibiting biofilm formation and quorum sensing. Additionally, it demonstrated a lower likelihood of resistance development, emphasizing its ability to fight multidrug-resistant pathogens. Given these promising findings, cyclic depsipeptides offer a promising molecular framework for addressing a range of human infections, particularly in an era of increasing antibiotic resistance. This review summarises the recently identified cyclic depsipeptide-based antimicrobial candidates for the treatment of bacterial, fungal, and parasitic infections.