Marine natural products for antifungal drug discovery: An updated review (2015–2025)

Fungal infections cause over 3.8 million deaths annually, yet existing antifungal classes, polyenes, azoles, echinocandins, and flucytosine, remain compromised by toxicity, narrow spectra, drug–drug interactions, and resistance, highlighting the need for structurally novel scaffolds. This review compiles 125 marine-derived antifungal natural products reported between June 2015 and December 2025, defining potency as MIC ≤ 10 μg/mL (or ≤ 10 μM) against human or phytopathogenic fungi. Marine fungi were the predominant producers (56%), followed by bacteria (25%); polyketides dominated chemically (38.4%), with alkaloids (21.6%), terpenoids (15.2) and peptides (11.2%). Recurring structure–activity determinants emerged across chemotypes: glycosylation and macrolactone integrity in 36-membered macrolides; fatty-acid chain length and terminal branching in lipopeptides and alkanoylimidazoles; C-7 halogenation and C-6 methoxylation in griseofulvins; hydroxylation pattern and ring fusion in pimarane diterpenes; and obligate Al(III)/Ga(III) chelation in acremonpeptide siderophores. Mechanistically, compounds converge on plasma-membrane destabilization and mitochondrial collapse, while several weakly active metabolites act as chemosensitizers restoring azole or amphotericin efficacy against resistant strains. Physicochemical profiling of 117 compounds using RDKit provided a preliminary drug-likeness overview, with ∼60% satisfying Lipinski’s rule of five, 66.7% meeting Veber’s criteria, and 42.7% passing the Ghose filter; 22 compounds showed comparatively favorable QED scores (≥0.7). These findings highlight marine natural products as a promising source of antifungal leads and outline the structural features and optimization needs relevant to their further development.