Pinpointing Pseurotins from a Marine-Derived <i>Aspergillus</i> as Tools for Chemical Genetics Using a Synthetic Lethality Yeast Screen

A new compound of mixed polyketide synthase–nonribosomal peptide synthetase (PKS/NRPS) origin, 11-<i>O</i>-methylpseurotin A (<b>1</b>), was identified from a marine-derived <i>Aspergillus fumigatus</i>. Bioassay-guided fractionation using a yeast halo assay with wild-type and cell cycle-related mutant strains of <i>Saccharomyces cerevisiae</i> resulted in the isolation of <b>1</b>, which selectively inhibited a Hof1 deletion strain. Techniques including 1D and 2D NMR, HRESIMS, optical rotation, <i>J</i>-based analysis, and biosynthetic parallels were used in the elucidation of the planar structure and absolute configuration of <b>1</b>. A related known compound, pseurotin A (<b>2</b>), was also isolated and found to be inactive in the yeast screen.