Towards novel herbicide modes of action by inhibiting lysine biosynthesis in plants

Tatiana P Soares da Costa,Saadi Bayat,Mark D Hulett,Matthew A Perugini,Rebecca M Christoff,Jessica A Wyllie,Santosh Panjikar,Cody J Hall,Belinda M Abbott,Anthony R Gendall

doi:10.7554/elife.69444

Abstract

Weeds are becoming increasingly resistant to our current herbicides, posing a significant threat to agricultural production. Therefore, new herbicides with novel modes of action are urgently needed. In this study, we exploited a novel herbicide target, dihydrodipicolinate synthase (DHDPS), which catalyses the first and rate-limiting step in lysine biosynthesis. The first class of plant DHDPS inhibitors with micromolar potency against Arabidopsis thaliana DHDPS was identified using a high-throughput chemical screen. We determined that this class of inhibitors binds to a novel and unexplored pocket within DHDPS, which is highly conserved across plant species. The inhibitors also attenuated the germination and growth of A. thaliana seedlings and confirmed their pre-emergence herbicidal activity in soil-grown plants. These results provide proof-of-concept that lysine biosynthesis represents a promising target for the development of herbicides with a novel mode of action to tackle the global rise of herbicide-resistant weeds.

Highlights

Our ability to provide food security for a growing world population is being increasingly challenged by the emergence and spread of herbicide resistant weeds
We show that these compounds display micromolar potency in vitro and in planta against A. thaliana using a combination of enzyme kinetics, seedling and soil assays, whilst exhibiting no cytotoxic effects in bacterial or human cell lines at equivalent concentrations
The lack of herbicides with novel modes of action entering the market in the past three decades has led to an over-reliance on our current agrichemicals, which has contributed to the rapid generation of resistance

Summary

Introduction

Our ability to provide food security for a growing world population is being increasingly challenged by the emergence and spread of herbicide resistant weeds. Resistance has been observed to the most widely used classes of herbicides. This includes amino acid biosynthesis inhibitors such as chlorsulfuron, glufosinate and glyphosate, which target enzymes in the biosynthetic pathways leading to the production of branched-chain amino acids, glutamine and aromatic amino acids, respectively (Duke, 2012; Hall et al, 2020; Heap, 2021, 2014; Vats, 2015). The successful commercialisation of such herbicides provides proof-of-concept that targeting the biosynthesis of amino acids offers an excellent strategy for herbicide development (Hall et al, 2020). Amino acids are essential building blocks for protein biosynthesis, but they play important roles in physiological processes that are critical for plant growth and development, such as carbon and nitrogen metabolism, in addition to serving as precursors to a wide range of secondary metabolites (Hildebrandt et al, 2015)

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Conclusion