Novel Chemistry from Thermophilic Fungi

Our lab is studying secondary metabolites from thermophilic fungi with novel structures and biological activities. We have reported that Talaromyces thermophilus, a thermophilic fungus collected from the Tengchong hot spring of Yunnan, China, produces the key biosynthetic precursors and intermediates, talathermophilins, which had long been proposed for the biosynthesis of TPS-NRPS hybrid prenylated tryptophan alkaloids but never have been isolated and identified. Further studies on the metabolic profiles of the thermophilic fungi T. thermophilus and Thermomyces lanuginosus revealed a novel class of PKS-NRPS hybrid molecules. These metabolites feature unprecedented PKS-NRPS hybrids containing a 13-membered lactam bearing macrolactone. Interestingly, thermolides A and B exhibit potent inhibitory activity against three types of nematodes including the root knot nematode Meloidogyne incognita, pine-wood nematode Bursaphelenches siylopilus, and free-living nematode Panagrellus redivevus with LC₅₀ values in the 0.5−1.0 μg/mL range, similar to those of avermectins. A combination of chemical screening, genome analyses, and genetic manipulation led to the identification of the thermolide biosynthetic genes from sister thermophilic fungi T. thermophilus and Thermomyces lanuginosus. The biosynthetic locus for the thermolides’ mixed polyketide-amino acid structure encodes a hybrid polyketide synthase−nonribosomal peptide synthetase (PKS−NRPS). Our results reveal the first fungal hybrid iterative PKS−NRPS genes involved in the biosynthesis of bacterial-like hybrid macrolactones instead of the typical fungal tetramic acids-containing metabolites.