Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity.

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dc.contributor.authorMackie, ERRen_AU
dc.contributor.authorBarrow, ASen_AU
dc.contributor.authorGiel, MCen_AU
dc.contributor.authorHulett, MDen_AU
dc.contributor.authorGendall, ARen_AU
dc.contributor.authorPanjikar, Sen_AU
dc.contributor.authorSoares da Costa, TPen_AU
dc.date.accessioned2023-12-22T00:31:23Zen_AU
dc.date.available2023-12-22T00:31:23Zen_AU
dc.date.issued2023-05-22en_AU
dc.date.statistics2023-06-06en_AU
dc.description.abstractHerbicide 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. We also showed that our lead compound is the first lysine biosynthesis inhibitor with activity against both monocotyledonous and dicotyledonous weed species, by demonstrating its effectiveness at reducing the germination and growth of Lolium rigidum (rigid ryegrass) and Raphanus raphanistrum (wild radish). These results provide 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. © The Authors - Open Access Creative Commons Attribution 4.0 International Licence.en_AU
dc.description.sponsorshipT.P.S.d.C. acknowledges the Australian Research Council for funding support through a DECRA Fellowship (DE190100806) and Discovery Project (DP220101901). Work in A.R.G.’s laboratory is supported by the Australian Research Council Research Hub for Medicinal Agriculture (IH180100006). E.R.R.M. acknowledges the Grains Research and Development Corporation (9176977) for support through a PhD scholarship and operational funding and the University of Adelaide for support through a Research Training Program scholarship. We thank Professor Christopher Preston (University of Adelaide, Australia) for providing wild radish seeds, Professor Ashley Franks (La Trobe University, Australia) for supplying bacterial isolates and Professor John Moses (La Trobe University, Australia) for providing infrastructure. We acknowledge the La Trobe University Comprehensive Proteomics Platform for providing infrastructure support. We acknowledge the use of the MX2 beamline at the Australian Synchrotron, part of ANSTO and employed the Australian Cancer Research Foundation (ACRF) detector.en_AU
dc.identifier.articlenumber550en_AU
dc.identifier.citationMackie, E. R. R., Barrow, A. S., Giel, M.-C., Hulett, M. D., Gendall, A. R., Panjikar, S., & Soares da Costa, T. P. (2023). Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity. Communications Biology, 6(1), 550. doi:10.1038/s42003-023-04895-yen_AU
dc.identifier.issn2399-3642en_AU
dc.identifier.issue1en_AU
dc.identifier.journaltitleCommunications Biologyen_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15299en_AU
dc.identifier.volume6en_AU
dc.language.isoenen_AU
dc.publisherSpringer Natureen_AU
dc.relation.urihttps://doi.org/10.1038/s42003-023-04895-yen_AU
dc.subjectHerbicidesen_AU
dc.subjectEnvironmenten_AU
dc.subjectAgricultureen_AU
dc.subjectEnzymesen_AU
dc.subjectLysineen_AU
dc.subjectWeedsen_AU
dc.subjectSoilsen_AU
dc.titleRepurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity.en_AU
dc.typeJournal Articleen_AU
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