Aclonifen targets solanesyl diphosphate synthase, representing a novel mode of action for herbicides

Abstract

BACKGROUND Aclonifen is a unique diphenyl ether herbicide. Despite its structural similarities to known inhibitors of the protoporphyrinogen oxidase (e.g. acifluorfen, bifenox or oxadiazon), which result in leaf necrosis, aclonifen causes a different phenotype that is described as bleaching. This also is reflected by the Herbicide Resistance Action Committee (HRAC) classification that categorizes aclonifen as an inhibitor of pigment biosynthesis with an unknown target. RESULTS A comprehensive Arabidopsis thaliana RNAseq dataset comprising 49 different inhibitor treatments and covering 40 known target pathways was used to predict the aclonifen mode of action (MoA) by a random forest classifier. The classifier predicts for aclonifen a MoA within the carotenoid biosynthesis pathway similar to the reference compound norflurazon that inhibits the phytoene desaturase. Upon aclonifen treatment, the phytoene desaturation reaction is disturbed, resulting in a characteristic phytoene accumulation in vivo. However, direct enzyme inhibition by the herbicide was excluded for known herbicidal targets such as phytoene desaturase, 4‐hydroxyphenylpyruvate dioxygenase and homogentisate solanesyltransferase. Eventually, the solanesyl diphosphate synthase (SPS), providing one of the two homogentisate solanesyltransferase substrate molecules, could be identified as the molecular target of aclonifen. Inhibition was confirmed using biochemical activity assays for the A. thaliana SPSs 1 and 2. Furthermore, a Chlamydomonas reinhardtii homolog was used for co‐crystallization of the enzyme–inhibitor complex, showing that one inhibitor molecule binds at the interface between two protein monomers. CONCLUSION Solanesyl diphosphate synthase was identified as the target of aclonifen, representing a novel mode of action for herbicides. © 2020 Society of Chemical Industry

Can new herbicide discovery allow weed management to outpace resistance evolution?

“…Although no new sites of action were introduced for a period of approximately 30 years, recently new sites of action have been identified for older herbicides and some entirely new herbicides with new sites of action have been reported. 52 These include the new groups 31 (inhibition of serine threonine protein phosphatase for endothall, 53 an aquatic herbicide discovered in the 1950s), 30 (inhibition of fatty acid thioesterase for cinmethlyin), 54 32 (inhibition of solanesyl diphosphate synthase for aclonifen), 55 and 33 (inhibition of homogentisate solanesyltransferase for cyclopyrimorate to control weeds in rice). 52 Additional new herbicides include tetflupyrolimet, an aryl pyrrolidinone anilide targeting dihydroorotate dehydrogenase, 56 a key enzyme in pyrimidine biosynthesis and aspterric acid targeting dihydroxy-acid dehydratasein branched chain amino acid synthesis.…”

Strategies for discovering resistance‐breaking, safe and sustainable commercial herbicides with novel modes of action and chemotypes

“…Illustrative examples being the following MoA elucidations, which took approximately 40 years: haloxydine as homogentisate solanesyl transferase (HST) in 2010 having been first reported in 1967, 13,14 cinmethylin as fatty acid thioesterase A (FatA) in 2018 having been first reported in 1983, 15,16 and aclonifen as solanesyl diphosphate synthase (SPS) in 2020 having being first reported in 1980. 17,18 4.4 Optimize chemistry Chemical optimization to transform herbicidal hits and leads into herbicidal candidates destined for full development is the most costly phase of the herbicide discovery process. Large amounts of money are spent on preparing hundreds or thousands of analogues to find the one candidate that meets most of the requirements for being the ideal herbicide mentioned in section 2.…”

Antibiotic resistance lessons for the herbicide resistance crisis

“…Tetflupyrolimet is targeted towards dihydroorotate dehydrogenase in grasses infesting rice fields and was developed by FMC Agricultural Solutions using a combination of metabolomics and forward genetics screens 64 . The recent discoveries of dihydroxy acid dehydratase as the target of aspterric acid, and solanyl diphosphate synthase as the target of aclonifen using a synthetic and systems biology approach also illustrate the potential application of ‐omics in herbicide discovery 65,66 . These approaches may also facilitate the design of herbicides that are tailored for multiple targets and produce a synergistic effect, as exemplified by antibacterial research 67–69 …”