A biosynthetic survey of hypocrealean biocontrol fungi

Pests cause up to 40% of global crops losses. Pesticide overuse drives resistance and poses notable risks to public health and the environment. Many hypocrealean fungi form symbiotic relationships with plants while antagonizing pests, making them valuable sources of biocontrol agents and biopesticides. However, little is known about their biosynthetic capabilities. Here we use phylogenomics, metabolomics and heterologous expression to catalog the biosynthetic repertoire of 82 plant-associated and insect-associated Hypocreales species. Annotation of 5,221 biosynthetic gene clusters reveals that ~80% of them encode unknown products. By linking biosynthetic gene clusters to molecules, we investigate the biosynthesis of several natural products, including pyridones, dethiosecoemestrin and efrapeptin. Additionally, by combining our metabologenomics workflow with synthetic biology, we characterize four nonribosomal peptide synthetase-like synthetases involved in the biosynthesis of hitherto unknown products. We believe that this work lays the groundwork for future efforts toward sustainable pest control in agriculture.