Fusaric Acid Analogs and Dimers from Marine-Derived Fusarium sp.: Biosynthetic Insights and Chloramphenicol-Enhanced Antibacterial Activity.

An investigation of the Hawaiian marine-derived fungus Fusarium sp. strain FM701 led to the isolation of two new pyridinium-containing fusaric acid dimers (1, 2), fusaric acid (3), and two known fusaric acid derivatives (4, 5), beauvericin (6), beauvericin J (7), and desferricrocin (8). Structures of 1 and 2 were elucidated by NMR spectroscopy, GIAO NMR calculations, HRESIMS, and electronic circular dichroism analyses. Genome mining revealed putative biosynthetic gene clusters for fusaric acid, beauvericin, and desferricrocin. Chemical synthesis of 9,10-dehydrofusaric acid (4) and racemic fusarinolic acid (5), combined with feeding experiments, supported their plausible biosynthetic relationship and potential roles as biosynthetic building blocks of dimeric metabolites 1 and 2. Compounds 1, 2, 6, and 7 exhibited potent antibacterial activity against Gram-positive bacteria, and all compounds (1-8) showed 2- to 4-fold enhanced activity when combined with a subinhibitory concentration of chloramphenicol. Beauvericin (6) also displayed strong antiproliferative activity against human breast (MCF-7) and prostate (DU145) cancer cell lines, with low micromolar IC50 values. Together, these findings expand the chemical diversity of fusaric acid metabolites and the biological potential of marine fungal metabolites.