Expanding antibiotic chemical space through precursor-directed biosynthesis

Nidulin is a fungal depsidone antibiotic first isolated in 1944 from the fungus Aspergillus nidulans. Nidulin shows potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have employed a combination of natural products chemistry, precursor-directed biosynthesis and chemical derivatisation to expand chemical space around the nidulin pharmacophore. Initial optimisation of culture media led to two new fungal metabolites, 7-carboxyfolipastatin and unguinolic acid, as well as four previously reported compounds. In precursor-directed biosynthesis experiments, Aspergillus unguis was supplemented with halide salts, leading to three new depsides, unguidepside A, unguidepside B and 5-bromoagonodepside B, and one new depsidone, 2-bromo-7-chlorounguinol. Finally, a semi-synthetic approach was employed to generate six nidulin analogues. All natural, unnatural and semi-synthetic compounds were screened for antibacterial, antifungal and cell cytotoxicity activities. Based on these bioassay results, a structure-activity relationship for the nidulin pharmacophore was proposed.