Hybridorubrins A–D: Azaphilone Heterodimers from Stromata of Hypoxylon fragiforme and Insights into the Biosynthetic Machinery for Azaphilone Diversification. Issue 4 (10th December 2020)

• Record Type: Journal Article
• Authors: Becker, Kevin; Pfütze, Sebastian; Kuhnert, Eric; Cox, Russell J.; Stadler, Marc; Surup, Frank
• Is Part Of: Chemistry. Volume 27:Issue 4(2021)
• Page Start: 1438
• Page End: 1450
• Publication Date: 2020-12-10
• Subjects: biosynthesis -- inhibitors -- natural products -- polyketides -- structure elucidation; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202003215
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The diversity of azaphilones in stromatal extracts of the fungus Hypoxylon fragiforme was investigated and linked to their biosynthetic machineries by using bioinformatics. Nineteen azaphilone‐type compounds were isolated and characterized by NMR spectroscopy and mass spectrometry, and their absolute stereoconfigurations were assigned by using Mosher ester analysis and electronic circular dichroism spectroscopy. Four unprecedented bis‐azaphilones, named hybridorubrins A–D, were elucidated, in addition to new fragirubrins F and G and various known mitorubrin derivatives. Only the hybridorubrins, which are composed of mitorubrin and fragirubrin moieties, exhibited strong inhibition of Staphylococcus aureus biofilm formation. Analysis of the genome of H. fragiforme revealed the presence of two separate biosynthetic gene clusters (BGCs) hfaza1 and hfaza2 responsible for azaphilone formation. While the hfaza1 BGC likely encodes the assembly of the backbone and addition of fatty acid moieties to yield the ( R )‐configured series of fragirubrins, the hfaza2 BGC contains the necessary genes to synthesise the widely distributed ( S )‐mitorubrins. This study is the first example of two distant cross‐acting fungal BGCs collaborating to produce two families of azaphilones and bis‐azaphilones derived therefrom. Abstract : Two become one ! Hybridorubrins A–D, unprecedented bis‐azaphilones isolated from the stromata of the ascomycete Hypoxylon fragiforme, are composed of mitorubrin‐ and fragirubrin‐type moieties. As revealed by genome analysis, two distantly located biosynthetic gene clusters work together to form these precursors. In contrast to their building blocks, the hybridorubrins exhibit strong inhibitory activity against biofilm formation of Staphylococcus aureus .