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.
Highlights
The Hypoxylaceae, which were recently resurrected in the course of a major phylogenetic study, are the second largest family of the [b] Dr E
We reported the occurrence of the novel azaphilones, fragirubrins A−E, as well as the bisazaphilones rutilins C−D, in stromata of H. fragiforme in addition to the known mitorubrins.[1b]. The present study deals with the isolation and identification of azaphilone heterodimers with interesting structural and biological features as well as the assignment of their biosynthesis genes
We used a combination of classical natural product chemistry and state-of-the-art genome sequencing to deduce the biosynthesis of azaphilone pigments in H. fragiforme, demonstrating the powerful combination of those two methods
Summary
The Hypoxylaceae, which were recently resurrected in the course of a major phylogenetic study, are the second largest family of the [b] Dr E. Taking the ECD results and the biosynthetic gene cluster (BGC) analysis (see Biosynthesis section below) into account allows for stereochemical assignment of the hetereodimers: rutilins like 12−13, which consist of two (S)-mitorubrin-type building blocks, are (S)-configured at both C-8 and C-8a.
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