Linking molecular architecture to antibacterial functions: a chemical biology view of cyclic depsipeptides

Antimicrobial depsipeptides and cyclodepsipeptides represent a structurally diverse class of natural products that have gained renewed attention as both antibacterial agents and molecular tools to interrogate bacterial physiology. Characterized by the incorporation of ester linkages within macrocyclic peptide frameworks, these molecules exhibit unique conformational properties that underpin distinct modes of action including lipid II recognition, membrane perturbation, and enzyme modulation. This review summarizes advances in discovery, chemical synthesis, and structure activity relationship studies across major depsipeptide families, highlighting how precise chemical features such as macrocycle topology, stereochemical configuration, hydroxylation patterns, and lipidation dictate biological function. By integrating mechanistic insights from chemical biology, microbiology, and medicinal chemistry, we illustrate how cyclodepsipeptides serve as privileged scaffolds for probing bacterial cell envelope organization and essential biosynthetic pathways. In the context of escalating antimicrobial resistance and limited innovation in small molecule antibiotics, these macrocyclic peptides offer valuable opportunities for mechanism driven probe development and therapeutic translation. Collectively, this article provides a unified framework linking molecular structure to antibacterial activity and aims to guide the rational design of next-generation peptide-based antibiotics.