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

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.
Competing Interests: TS, BA, MP is listed as an inventor on a patent pertaining to inhibitors described in the manuscript. Patent Title: Heterocyclic inhibitors of lysine biosynthesis via the diaminopimelate pathway; International patent (PCT) No.: WO2018187845A1; Granted: 18/10/2018. CH, SP, JW, RC, SB, MH, AG No competing interests declared
(© 2021, Soares da Costa et al.)