title: High resolution genetic mapping uncovers chitin synthase-1 as the target-site of the structurally diverse mite growth inhibitors clofentezine, hexythiazox and etoxazole in Tetranychus urticae.
abstract: The acaricides clofentezine, hexythiazox and etoxazole are commonly referred to as 'mite growth inhibitors', and clofentezine and hexythiazox have been used successfully for the integrated control of plant mite pests for decades. Although they are still important today, their mode of action has remained elusive. Recently, a mutation in chitin synthase 1 (CHS1) was linked to etoxazole resistance. In this study, we identified and investigated a Tetranychus urticae strain (HexR) harboring recessive, monogenic resistance to each of hexythiazox, clofentezine, and etoxazole. To elucidate if there is a common genetic basis for the observed cross-resistance, we adapted a previously developed bulk segregant analysis method to map with high resolution a single, shared resistance locus for all three compounds. This finding indicates that the underlying molecular basis for resistance to all three compounds is identical. This locus is centered on the CHS1 gene, and as supported by additional genetic and biochemical studies, a non-synonymous variant (I1017F) in CHS1 associates with resistance to each of the tested acaricides in HexR. Our findings thus demonstrate a shared molecular mode of action for the chemically diverse mite growth inhibitors clofentezine, hexythiazox and etoxazole as inhibitors of an essential, non-catalytic activity of CHS1. Given the previously documented cross-resistance between clofentezine, hexythiazox and the benzyolphenylurea (BPU) compounds flufenoxuron and cycloxuron, CHS1 should be also considered as a potential target-site of insecticidal BPUs.
authors.affiliation: Department of Crop Protection, Faculty of Bioscience Engineering, Coupure Links 653, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Demaeght
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, 257 South 1400 East, Utah 84112, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Osborne
authors.affiliation: Department of Biology/Chemistry, University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany.
authors.forename: Jothini
authors.initials: J
authors.lastname: Odman-Naresh
authors.affiliation: Department of Biology, The University of Western Ontario, 1151 Richmond St., London N6A 5B7, Canada; Instituto de Ciencias de la Vid y el Vino, 26006 Logroño, Spain.
authors.forename: Miodrag
authors.initials: M
authors.lastname: Grbić
authors.affiliation: R&D, Pest Control Biology, Bayer CropScience, Alfred Nobel Str. 50, D-40789 Monheim, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Nauen
authors.affiliation: Department of Biology/Chemistry, University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Merzendorfer
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, 257 South 1400 East, Utah 84112, USA; Center for Cell and Genome Science, University of Utah, Salt Lake City, 257 South 1400 East, Utah 84112, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Clark
authors.affiliation: Department of Crop Protection, Faculty of Bioscience Engineering, Coupure Links 653, Ghent University, B-9000 Ghent, Belgium; Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands. Electronic address: thomas.vanleeuwen@ugent.be.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Leeuwen
mesh_terms: D056810:Acaricides / Q000494:pharmacology*; D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D002686:Chitin / Q000037:antagonists & inhibitors; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D002722:Chlorobenzenes / Q000494:pharmacology*; D002874:Chromosome Mapping; D020090:Chromosome Segregation; D006131:Growth Inhibitors; D010080:Oxazoles / Q000494:pharmacology*; D040102:Tetranychidae / Q000235:genetics* / Q000254:growth & development*; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: C583328:5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3 carboxamide; D056810:Acaricides; D002722:Chlorobenzenes; D006131:Growth Inhibitors; D010080:Oxazoles; D053778:Thiazolidines; D002686:Chitin; D002687:Chitin Synthase; C062106:clofentezine; C508136:etoxazole
keywords: Chitin synthesis inhibitors; Fukui function; Genetic mapping; Insecticide; Mite growth inhibitors