Sponge Derived Macrolides (2000-2023): Chemical Diversity, Mechanistic Insights and Therapeutic Potential

Macrolides, a class of antibiotics commonly used in clinical practice, have been derived from naturally occurring compounds found in marine sponges. This narrative mini-review covers the period from 2000 to 2023, focusing on the chemical, mechanistic insights, and therapeutic potential of 96 novel macrolide compounds isolated from marine sponge species. These metabolites have structurally intricate macrocyclic lactone structures, often featuring polyene chains, spiroketal systems, tetrahydropyran units, glycosidic components, and halogen substituents that enhance their biological efficacy and target selectivity. Sponge-derived macrolides exhibit significant cytotoxic, anticancer, antibacterial, antifungal, and anti-inflammatory properties, with several compounds showing nanomolar potency against drug-resistant cancer cell lines. Mechanistic studies identify various molecular targets, such as the control of microtubule dynamics, disruption of actin filaments, induction of mitochondrial-mediated apoptosis, suppression of protein synthesis, and regulation of the PI3K/Akt and MAPK signalling pathways. Recent trends in structure-activity relationships reveal that macrocycle size, conformational rigidity, stereochemical arrangement, and functional group distribution significantly affect potency and selectivity. Several sponge-derived macrolides and their synthetic analogues have notably progressed into preclinical evaluation, showing promising in vivo antitumor efficacy and enhanced pharmacokinetic profiles. Nevertheless, obstacles such as restricted natural availability, intricate structural characteristics, scalability issues in synthesis, and the need for enhanced safety margin optimization continue to hinder clinical translation. Ongoing advancements in total synthesis, semisynthetic modification, biosynthetic engineering, and formulation strategies are anticipated to expedite their movement towards marine drug development.