A Novel Mechanism of Herbicide Action

What is it about?

The article describes the discovery of a new herbicide mode of action, or most simply, a molecular target by which a small molecule exerts an inhibitory effect on the growth of a weed. Such discoveries are exceedingly rare in the agrochemical industry, the last new herbicide mode of action having been described decades ago. Fortunately, a new molecule emerged from our plant biology screens with weak but unusual herbicidal properties. Following synthetic optimization, the resulting analog, tetflupyrolimet, demonstrated both improved potency on key grass weed species and was selectively safe for rice. The well-known targets of commercial herbicides were found not to be implicated in this as yet undefined mode of action however, screening of chemically mutated Arabidopsis seed lines provided a plant isolate that was resistant to the new active molecule. Using a combination of genomic sequencing of resistant Arabidopsis seedlings and metabolite monitoring of treated plants, we identified both the biosynthetic pathway disrupted by the new molecule as pyrimidine (a DNA precursor) biosynthesis and also the specific enzymatic step in the pathway that was inhibited (dihydroorotate dehydrogenase, or DHODH). Subsequent production of plant DHODH in bacterial hosts produced high purity protein of enough quality to validate the interaction of tetflupyrolimet with this enzyme in vitro, and to generate high resolution molecular structures of the enzyme with bound inhibitor, providing a structural basis of the interaction between protein and ligand and thus an understanding of the new herbicidal mechanism.

Featured Image

Photo by Alexey Marchenko on Unsplash

Photo by Alexey Marchenko on Unsplash

Why is it important?

Delivery of the amount of food needed annually to support the worlds growing population, estimated to be about 1.3 million souls per week, requires those in agricultural R&D, academia and industry to constantly search for new ways of combating weeds and pests that without chemical control would decimate the world’s food supply. Loss of effectiveness of the current portfolio of commercial agrochemicals due to either new pests emerging or selection of resistant biotypes from existing field populations is a constant challenge for our industry. Growers are in constant need of new mode of action chemistries to assist in their pest management programs. Tetflupyrolimet represents a new class of chemistry which binds to a new molecular target for herbicides and will thus provide effective control of grass weeds resistant to current herbicide offerings.

Perspectives