The impact and prospect of natural product discovery in agriculture: New technologies to explore the diversity of secondary metabolites in plants and microorganisms for applications in agriculture

Abstract

Natural products from plants and microorganisms are potent bioactive molecules that have been used in medicine, agriculture and cosmetics. Genomics and synthetic biology offer new tools to further explore their diversity for applications as fungicides or herbicides.

Figure 1. Microbial NPs that are used as pesticides

The bioactivities (red) and sources (blue) of NP or NP‐derived molecules.

Figure 2. Examples of co‐localization of biosynthetic gene clusters (BGCs) and target enzymes

(A) Microorganisms produce NPs (black triangles) to kill competitors by inhibiting essential metabolic enzymes (yellow spheres). The organism produces self‐resistance enzymes (SRE, red spheres) that are able to complement the function of the targeted metabolic enzymes for survival. (B) Representative BGCs show co‐localization of biosynthetic core enzymes for lovastatin (blue) and self‐resistance genes of HMG‐CoA reductase in eukaryotes (red). The fungus A. terreus that produces lovastatin has a second copy of HMGR encoded by ORF8 in the gene cluster; BGC of the fatty acid synthase inhibitor thiolactomycin from Salinispora pacifica was located using a second copy of fatty acid synthase, which was further proved to be a SRE. The antituberculosis agent griselimycin was found to target DNA polymerase, hinted by the presence of a self‐resistance gene that encodes DNA polymerase in its BGC. A natural herbicide aspterric acid was discovered using resistance gene‐directed approach. (C) The structure of NPs relevant to (B).

Figure 3. Workflow of resistance gene‐guided discovery of NP herbicide aspterric acid (AA)

Figure 4. Strategies for diversity‐oriented biosynthesis

(A) Precursor‐directed biosynthesis and mutasynthesis to obtain “unnatural” NPs. (B) Mixing and matching biosynthetic pathways to produce NP derivatives. (C) Representative antimycin derivatives produced using combinatorial strategies of diversity‐oriented biosynthesis.