Antibacterial Depsipeptides: One Common Feature, Diversity of Structures and Mechanisms of Action

The emergence and spread of drug-resistant pathogens have made the development of new antibiotics a global priority. Innovative agents with new mechanisms of action and/or membership in new drug classes are urgently needed. Antimicrobial peptides have been widely studied and show promise as therapeutics. Depsipeptides are a large group of peptides in which one or more amide bonds are replaced by ester bonds. They are nonribosomal peptides that typically contain up to 20 amino acids, often arranged in cyclic scaffolds with diverse side chains, and they display varied biological activities. Many depsipeptide antibiotics have now been identified, and this class merits focused attention. This review surveys roughly two dozen compounds with pronounced antibacterial properties that have been discovered or actively investigated in recent years. These include daptomycin, a clinically important systemic antibiotic; teixobactin, a candidate in clinical development; acyldepsipeptides, which are preclinical leads; and several recent hits with drug-development potential, such as clovibactin, lysocin E, ecumicin, and empedopeptin. We also discuss ramoplanin, which underwent clinical evaluation but is no longer considered a leading candidate, and the enniatins, once used clinically but now recognized as mycotoxins. The review focuses primarily on mechanisms of action and summarizes each compound to the extent these mechanisms have been characterized.