From bacteria to plants: a repurposing strategy in the pursuit for novel herbicides

Abstract

Herbicide resistance represents one of the biggest threats to our natural environment and agricultural sector. Thus, new herbicides are urgently needed to tackle the rise in herbicide-resistant weeds. Here, we employed a novel strategy to repurpose a ′failed′ antibiotic into a new and target-specific herbicidal compound. Specifically, we identified an inhibitor of bacterial dihydrodipicolinate reductase (DHDPR), an enzyme involved in lysine biosynthesis in plants and bacteria, that exhibited no antibacterial activity but severely attenuated germination of the plant Arabidopsis thaliana. We confirmed that the inhibitor targets plant DHDPR orthologues in vitro, and exhibits no toxic effects against human cell lines. A series of analogues were then synthesised with improved efficacy in germination assays and against soil-grown A. thaliana plants. We also showed that our lead compound is the first lysine biosynthesis inhibitor with herbicidal activity against a weed species, providing proof-of-concept that DHDPR inhibition may represent a much-needed new herbicide mode of action. Furthermore, this study exemplifies the untapped potential of repurposing ′failed′ antibiotic scaffolds to fast-track the development of herbicide candidates targeting the respective plant enzymes to combat the global rise in herbicide-resistant weeds.

A dual-target herbicidal inhibitor of lysine biosynthesis

“…Recombinant AtDHDPS1, AtDHDPS2, AtDHDPR1, and AtDHDPR2 proteins were produced as previously described ( Mackie et al, 2022 ; Soares da Costa et al, 2021 ).…”

“…DHDPS enzyme activity was measured using methods previously described ( Soares da Costa et al, 2021 ). DHDPR enzyme activity was measured using methods previously described ( Mackie et al, 2022 ). Briefly, reaction mixtures were incubated at 30℃ for 12 min before a second 60-s incubation following the addition of excess E. coli DHDPS (51 µg ml −1 ) for generation of the DHDP substrate.…”

“…The herbicidal efficacy of MBDTA-2 against L. rigidum was assessed using methods similar to those reported previously ( Mackie et al, 2022 ). Pre-wet seed-raising soil (pH 5.5) (Biogro, Dandenong South, VIC, Australia) supplemented with 0.22% (wt/wt) Nutricote N12 Micro 140 day-controlled release fertiliser (Yates, Sydney, NSW, Australia) was used.…”

A dual-target herbicidal inhibitor of lysine biosynthesis

“…DHDPS enzyme activity was measured using methods previously described (Soares da Costa et al, 2021). DHDPR enzyme activity was measured using methods previously described (Mackie et al, 2022). Briefly, reaction mixtures were incubated at 30 °C for 12 min before a second 60 s incubation following the addition of excess E. coli DHDPS (51 μg·mL −1 ) for generation of the DHDP substrate.…”

“…The herbicidal efficacy of MBDTA-2 against L. rigidum was assessed using methods similar to those reported previously (Mackie et al, 2022). Pre-wet seed-raising soil (pH 5.5) (Biogro, Dandenong South, VIC, Australia) supplemented with 0.22% (w/w) Nutricote N12 Micro 140 day-controlled release fertiliser (Yates, Sydney, NSW, Australia) was used.…”