Surugamides: Structural Diversity, Biosynthesis, Chemical Synthesis, Structural Characterization, and Pharmacological Potential

Abstract

Surugamides are non-ribosomal peptides produced by Streptomyces species that display remarkable structural diversity, including cyclic, bicyclic, and linear analogues containing D- and Lamino acids and non-proteinogenic residues such as 3-amino-2-methylpropionic acid (AMPA), which contribute to their stability and biological properties. Their biosynthesis is directed by distinct non-ribosomal peptide synthetase (NRPS) gene pairs, SurA/SurD and SurB/SurC, responsible for cyclic and linear analogues, respectively, while peptide release is catalyzed by the trans-acting enzyme SurE, which functions as either a cyclase or thioesterase. Advances in mass spectrometry (MS), nuclear magnetic resonance (NMR), and Marfey analysis have improved the structural characterization of surugamides, enabling stereochemical assignments and important structural revisions, particularly for surugamides A and F. In parallel, genomic and metabolomic approaches have expanded the discovery of new congeners, whereas chemoenzymatic strategies have enabled analogue production, structural refinement, and structure-activity relationship studies. Surugamides exhibit diverse biological activities, including antibacterial, antifungal, cytotoxic, and anthelmintic effects. This review summarizes advances reported between 2013 and 2025 regarding the biosynthesis, synthesis, structural characterization, and pharmacological potential of this promising peptide class, while highlighting challenges and opportunities for its future therapeutic development.