Fusidane-type antibiotics represented by helvolic acid, fusidic acid and cephalosporin P1 are a class of bacteriostatic agents, which have drawn renewed attention because they have no cross-resistance to commonly used antibiotics. However, their biosynthesis is poorly understood. Here, we perform a stepwise introduction of the nine genes from the proposed gene cluster for helvolic acid into Aspergillus oryzae NSAR1, which enables us to isolate helvolic acid (~20 mg L-1) and its 21 derivatives. Anti-Staphylococcus aureus assay reveals that the antibacterial activity of three intermediates is even stronger than that of helvolic acid. Notably, we observe an unusual C-4 demethylation process mediated by a promiscuous short-chain dehydrogenase/reductase (HelC) and a cytochrome P450 enzyme (HelB1), which is distinct from the common sterol biosynthesis. These studies have set the stage for using biosynthetic approaches to expand chemical diversity of fusidane-type antibiotics.
CITATION STYLE
Lv, J. M., Hu, D., Gao, H., Kushiro, T., Awakawa, T., Chen, G. D., … Yao, X. S. (2017). Biosynthesis of helvolic acid and identification of an unusual C-4-demethylation process distinct from sterol biosynthesis. Nature Communications, 8(1). https://doi.org/10.1038/s41467-017-01813-9
Mendeley helps you to discover research relevant for your work.