Halogenated meroterpenoids with antifungal activities from the Deep-Sea-Derived fungus Acremonium sclerotigenum guided by the genomic and OSMAC strategy

Thirteen new meroterpenoids, acremorins A-M (1, 2, 4, 6, 7 and 9-16), together with three known analogues (3, 5 and 8) were isolated from the deep-sea-derived fungus Acremonium sclerotigenum LW14 guided by the genomic and OSMAC strategy. Their structures and absolute configurations were established by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculations, Rh₂(OCOCF₃)₄-induced ECD experiments, and a single-crystal X-ray diffraction experiment. Compounds 2, 4, 6 and 9 represent the rare brominated ascochlorins. Compounds 1/3 and 2/4 are two pairs of epimers isomerized at C-19. Compounds 1 and 2 are the first examples of ascochlorins which have the 19S configuration in the cyclohexanone moiety. Compounds 3/7, 8/10 and 11/12 are three pairs of epimers isomerized at C-12, C-18 and C-15, respectively. Compounds 7-10 showed moderate Antifungal activity against Cryptococcus gattii 3271G1 with the same MIC values of 8 μg/mL. The treatment with compound 7 led to a significant reduction in the cell wall thickness, rarefaction of cytoplasm, and damage to the structural integrity of organelles in C. gattiii 3271G1. Further RNA Sequencing (RNA seq) analysis indicated that compound 7 exerted its anti-C. gattiii effect by up-regulating the biosynthesis and RNA binding of ribosomes, while concurrently inhibiting RNA and nucleic acid metabolism and ATPase activity.

Antifungal activity; Deep-sea-derived fungus; Genomic; Halogenated meroterpenoids; OSMAC.