Expanding antibiotic chemical space through precursor-directed biosynthesis

The rapid emergence of multidrug-resistant microorganisms demands continuous development of new antibiotics with novel modes of action. However, very few candidates are currently in the pipeline. The present study addresses this challenge by combining natural product chemistry, precursor-directed biosynthesis and chemical derivatisation to expand the chemical space around nidulin, an antibiotic depsidone first isolated from Aspergillus nidulans in 1944. 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 fed unnatural salicylic acid and orsellinic acid derivatives, which did not yield any new nidulin analogues. However, supplementing the culture medium with halide salts led 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. Among the new depsides and depsidones, 2-bromo-7-chlorounguinol showed good antibacterial activity (IC50 2.8 μg/mL), while 2,4-diiodo-1ʹ,2ʹ-dihydrounguinol exhibited the highest antibacterial activity (IC50 0.99 μg/mL) against Bacillus subtilis among the all synthetic compounds. A structure-activity relationship for the nidulin pharmacophore was proposed.