Evaluation and Development of Spinosyns to Control Ectoparasites on Cattle and Sheep

Kirst, Herbert A.; Creemer, Lawrence C.; Naylor, Sharon A.; Pugh, Paul T.; Snyder, Daniel E.; Winkle, Joseph R.; Lowe, L. B.; Rothwell, J.; Sparks, Thomas C.; Worden, Thomas V.

doi:10.2174/1568026023393615

Cited by 37 publications

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“…11 In addition, the National Cancer Institute has invested considerable effort in evaluating the inhibitory activity of pepstatin on HIV-1 (human immunodeficiency virus-1). Pepstatin A is a small pentapeptide produced by several Streptomyces species with a unique hydroxyamino acid (statine) that sterically blocks the active site of HIV-1 protease.…”

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confidence: 99%

Carbon source regulation of antibiotic production

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Carbon source regulation of antibiotic production

et al. 2010

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“…1), which are the major active components of the flea product spinosad (Kirst et al, 2002). This insecticide is largely used in agriculture to control insects and mites.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of speed and duration of efficacy of spinosad tablets for treatment and control ofCtenocephalides canis(Siphonaptera: Pulicidae) infestations in dogs

Franc

Bouhsira

2009

Parasite

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Summary :A controlled clinical trial was performed to determine the duration of efficacy of a new oral insecticide formulation of spinosad for the control of experimentally induced Ctenocephalides canis infestations in dogs. Twelve Beagle dogs (two groups of six) were used in the study. Dogs in the treated group received spinosad tablets per os on D0 at the commercial dosage. All dogs were infested with 100 fleas on 7, 14, 21, 28 and 35. The dogs were combed four hours after each infestation and fleas were counted and replaced on the coat. 24 hours after each infestation fleas were combed, counted and removed. The efficacy of the formulation was calculated four and 24 hours after the treatment and then four and 24 hours after each new infestation. The mean number of fleas on the control dogs was respectively between 65.1 and 83.3 at four hour counts and between 58.3 and 75.3 at 24 hour counts. The product was well tolerated. The treatment controlled the fleas already present on the skin with 81 % efficacy at four hours and 100 % efficacy at 24 hours. For the weekly infestations, the speed of action of the product was high: at four hours the efficacy was 100 % at D7, 96 % at D14, 74 % at D21, 42 % at D28, 12.90 % at D35 and 12.8 % at D42. The efficacy evaluated 24 hours after each infestation was approximately 100 % during three weeks then 90 % at D39, 81.4 % at D36 and 80.4 % at D43. A single dose of the new spinosad tablet formulation should control flea populations in dogs for four weeks as indicated in the claim (evaluation performed at 48 h for the registration). Spinosad tablet is the first product administered per os which acts so long and so quickly against adult fleas. Résumé

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“…Spinosyns have thus attracted increasing efforts on structural modifications to improve their insecticidal activity as well as to prevent possible resistance problems (2,3). Structurally, spinosyns are novel glycosylated macrolides consisting of a 21-carbon tetracyclic lactone decorated with tri-O-methyl-Lrhamnose and D-forosamine (see Scheme 1).…”

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confidence: 99%

“…Structurally, spinosyns are novel glycosylated macrolides consisting of a 21-carbon tetracyclic lactone decorated with tri-O-methyl-Lrhamnose and D-forosamine (see Scheme 1). The tetracyclic aglycone scaffold is delicately constructed first by type I polyketide (PK-I) 2 synthases, followed by proposed postmodification events, including FAD-oxidation at C-15, Michael addition between C-3 and C-14, ␥-dehydration at C-11, and Diels-Alder cyclization (4,5). The spinosyn biosynthesis genes recently cloned and sequenced are located in an ϳ80-kb cluster of the S. spinosa genome, except that the four genes involved in L-rhamnose (L-Rha) biosynthesis, gtt (NDP-glucose synthase), gdh (NDP-glucose 4,6-dehydratase), epi (NDP-4-keto-6-deoxyglucose epimerase), and kre (NDP-4-ketorhamnose reductase), are located in three different regions of the genome (6).…”

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confidence: 99%

“…However, none of the above observations has ever been demonstrated directly in vitro or at the enzymatic level of biotransformation. Moreover, it has been shown that L-Rha is absolutely required for the reported insecticidal activity, and its alteration can improve insecticidal activity (2). Nonetheless, spinosyn derivatives generated of this kind are still limited and are restricted to in vivo experiments only.…”

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Functional Characterization and Substrate Specificity of Spinosyn Rhamnosyltransferase by in Vitro Reconstitution of Spinosyn Biosynthetic Enzymes

Chen

Lin

et al. 2009

Journal of Biological Chemistry

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Spinosyn, a potent insecticide, is a novel tetracyclic polyketide decorated with D-forosamine and tri-O-methyl-L-rhamnose. Spinosyn rhamnosyltransferase (SpnG) is a key biocatalyst with unique sequence identity and controls the biosynthetic maturation of spinosyn. The rhamnose is critical for the spinosyn insecticidal activity and cell wall biosynthesis of the spinosyn producer, Saccharopolyspora spinosa. In this study, we have functionally expressed and characterized SpnG and the three enzymes, Gdh, Epi, and Kre, responsible for dTDP-L-rhamnose biosynthesis in S. spinosa by purified enzymes from Escherichia coli. Most notably, the substrate specificity of SpnG was thoroughly characterized by kinetic and inhibition experiments using various NDP sugar analogs made by an in situ combination of NDP-sugar-modifying enzymes. SpnG was found to exhibit striking substrate promiscuity, yielding corresponding glycosylated variants. Moreover, the critical residues presumably involved in catalytic mechanism of Gdh and SpnG were functionally evaluated by site-directed mutagenesis. The information gained from this study has provided important insight into molecular recognition and mechanism of the enzymes, especially SpnG. The results have made possible the structureactivity characterization of SpnG, as well as the use of SpnG or its engineered form to serve as a combinatorial tool to make spinosyn analogs with altered biological activities and potency.Spinosad, a mixture of spinosyns A and D (ϳ85 and 15%, respectively) produced by the actinomycete Saccharopolyspora spinosa, has been proven highly effective against many chewing insect pests and designated as a reduced risk pesticide excellent in both environmental and mammalian toxicological considerations (1). Spinosyns have thus attracted increasing efforts on structural modifications to improve their insecticidal activity as well as to prevent possible resistance problems (2, 3). Structurally, spinosyns are novel glycosylated macrolides consisting of a 21-carbon tetracyclic lactone decorated with tri-O-methyl-Lrhamnose and D-forosamine (see Scheme 1). The tetracyclic aglycone scaffold is delicately constructed first by type I polyketide (PK-I) 2 synthases, followed by proposed postmodification events, including FAD-oxidation at C-15, Michael addition between C-3 and C-14, ␥-dehydration at C-11, and Diels-Alder cyclization (4, 5). The spinosyn biosynthesis genes recently cloned and sequenced are located in an ϳ80-kb cluster of the S. spinosa genome, except that the four genes involved in L-rhamnose (L-Rha) biosynthesis, gtt (NDP-glucose synthase), gdh (NDP-glucose 4,6-dehydratase), epi (NDP-4-keto-6-deoxyglucose epimerase), and kre (NDP-4-ketorhamnose reductase), are located in three different regions of the genome (6). Previous genetic experiments have suggested that the polyketide aglycone is biosynthesized prior to immediate attachment of L-Rha by the rhamnosyltransferase SpnG, followed by consecutive tri-O-methylation of the L-Rha on resulting spinosyn rhamnosyl pseudoa...

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Evaluation and Development of Spinosyns to Control Ectoparasites on Cattle and Sheep

Cited by 37 publications

References 0 publications

Carbon source regulation of antibiotic production

Carbon source regulation of antibiotic production

Evaluation of speed and duration of efficacy of spinosad tablets for treatment and control ofCtenocephalides canis(Siphonaptera: Pulicidae) infestations in dogs

Functional Characterization and Substrate Specificity of Spinosyn Rhamnosyltransferase by in Vitro Reconstitution of Spinosyn Biosynthetic Enzymes

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