The biosynthetic logic and enzymatic machinery of approved fungi-derived pharmaceuticals and agricultural biopesticides

Covering: 2000 to 2023

The kingdom Fungi has become a remarkably valuable source of structurally complex natural products (NPs) with diverse bioactivities. Since the revolutionary discovery and application of the antibiotic penicillin from Penicillium, a number of fungi-derived NPs have been developed and approved into pharmaceuticals and pesticide agents using traditional “activity-guided” approaches. Although emerging genome mining algorithms and surrogate expression hosts have brought revolutionary approaches to NP discovery, the time and costs involved in developing these into new drugs can still be prohibitively high. Therefore, it is essential to maximize the utility of existing drugs by rational design and systematic production of new chemical structures based on these drugs by synthetic biology. To this purpose, there have been great advances in characterizing the diversified biosynthetic gene clusters associated with the well-known drugs and in understanding the biosynthesis logic mechanisms and enzymatic transformation processes involved in their production. We describe advances made in the heterogeneous reconstruction of complex NP scaffolds using fungal polyketide synthases (PKSs), non-ribosomal peptide synthetases (NRPSs), PKS/NRPS hybrids, terpenoids, and indole alkaloids and also discuss mechanistic insights into metabolic engineering, pathway reprogramming, and cell factory development. Moreover, we suggest pathways for expanding access to the fungal chemical repertoire by biosynthesis of representative family members via common platform intermediates and through the rational manipulation of natural biosynthetic machineries for drug discovery.