Harnessing the Mixing Power of the Microbial Secondary Metabolites Kaleidoscope: Bacterial Hybrid Terpene Biosynthetic Pathways

• Applicants: Professor Dr. Andriy Luzhetskyy; Professor Dr. Rolf Müller
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms ; Pharmacy
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468811723

Bacterial terpenoid metabolites have long-time been neglected as source of natural products. Comparing to the enormous numbers of terpene compounds discovered from plants and fungi and considering terpenes as the largest class of natural products, it is surprising that terpenoids are rarely isolated from bacteria. Even more striking, whole-genome sequencing of two of the most proficient producer classes, actinobacteria and myxobacteria, show them to harbor a large number of terpene or hybrid terpene biosynthetic gene clusters (BGCs), most of which are of currently unknown function. Both bacterial clades thus display enormous hidden biosynthetic potential for the production of many more specialized metabolites as candidates for chemical biology tools and even drug leads. Recently, we have isolated chemically novel and promising terpenoids and complex polyketide/nonribosomal peptide/terpene hybrid molecules from myxobacteria and actinobacteria exhibiting potent bioactivities including inhibition of coronaviruses. We here aim to further explore the potential for producing novel and bioactive terpenoids from myxobacteria and rare actinobacteria (e.g. Frankia, Kutzneria, Saccharothrix). However, these bacteria are notoriously difficult to manipulate genetically, and grow relatively slowly, thus largely hindering the exploration using genetic engineering of native producers. This joint project therefore intends to transfer respecitve BGCs into amenable heterologous hosts to discover novel specialized metabolites. The Chinese side will make use of their pioneering Red/ET recombineering-mediated direct cloning technology (LLHR and ExoCET) to directly capture large BGCs, and integrate the German side’s advantages in myxobacterial and actinobacterial molecular biology and genetics, metabolite chemical analytics, biosynthetic know-how, and mode-of-action activities, to discover and characterize novel bioactive terpenoids. Intriguing steps of the biosynthetic pathways will be characterized in vivo and in vitro. Based on our previous successful cooperation in heterologous production of several known myxobacterial and actinobacterial compounds, we will expand our work to discover novel bioactive compounds from cryptic BGCs. This project is thus expected to unlock access to a number of otherwise hardly- or even non-accessible complex natural products exhibiting potential anti-infective and anticancer drug lead activity. This project will certainly strengthen the scientific collaboration between our three institutes, improve scientific productivity, develop and exchange qualified personnel, and promote friendly relations and cooperation between our two countries.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partner: Professor Dr. Youming Zhang, Ph.D.