Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity

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dc.contributor.authorMackie, E.R.R.
dc.contributor.authorBarrow, A.S.
dc.contributor.authorGiel, M.-C.
dc.contributor.authorHulett, M.D.
dc.contributor.authorGendall, A.R.
dc.contributor.authorPanjikar, S.
dc.contributor.authorSoares da Costa, T.P.
dc.date.issued2023
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.
dc.description.statementofresponsibilityEmily R. R. Mackie, Andrew S. Barrow, Marie-Claire Giel, Mark D. Hulett, Anthony R. Gendall, Santosh Panjikar, Tatiana P. Soares da Costa
dc.identifier.citationCommunications Biology, 2023; 6(1):1-11
dc.identifier.doi10.1038/s42003-023-04895-y
dc.identifier.issn2399-3642
dc.identifier.issn2399-3642
dc.identifier.orcidMackie, E.R.R. [0000-0002-0851-5741]
dc.identifier.orcidBarrow, A.S. [0000-0003-3661-5173]
dc.identifier.orcidSoares da Costa, T.P. [0000-0002-6275-7485]
dc.identifier.urihttps://hdl.handle.net/2440/140300
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/arc/DE190100806
dc.relation.granthttp://purl.org/au-research/grants/arc/DP220101901
dc.relation.granthttp://purl.org/au-research/grants/arc/IH180100006
dc.rights© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s42003-023-04895-y
dc.subjectEnzymes; plant sciences
dc.subject.meshHumans
dc.subject.meshBacteria
dc.subject.meshArabidopsis
dc.subject.meshLysine
dc.subject.meshHerbicides
dc.subject.meshDihydrodipicolinate Reductase
dc.subject.meshPlant Weeds
dc.titleRepurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity
dc.typeJournal article
pubs.publication-statusPublished

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