Spinosyns

Spinosyn A

Spinosyn D
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.103.254 Edit this at Wikidata
KEGG
UNII
  • A: InChI=1S/C41H65NO10/c1-10-26-12-11-13-34(52-36-17-16-33(42(5)6)23(3)48-36)22(2)37(44)32-20-30-28(31(32)21-35(43)50-26)15-14-25-18-27(19-29(25)30)51-41-40(47-9)39(46-8)38(45-7)24(4)49-41/h14-15,20,22-31,33-34,36,38-41H,10-13,16-19,21H2,1-9H3/t22-,23-,24+,25-,26+,27-,28-,29-,30-,31+,33+,34+,36+,38+,39-,40-,41+/m1/s1
    Key: SRJQTHAZUNRMPR-UYQKXTDMSA-N
  • D: InChI=1S/C42H67NO10/c1-11-26-13-12-14-35(53-37-16-15-34(43(6)7)24(4)49-37)23(3)38(45)33-20-31-29(32(33)21-36(44)51-26)17-22(2)28-18-27(19-30(28)31)52-42-41(48-10)40(47-9)39(46-8)25(5)50-42/h17,20,23-32,34-35,37,39-42H,11-16,18-19,21H2,1-10H3/t23-,24-,25+,26+,27-,28+,29-,30-,31-,32+,34+,35+,37+,39+,40-,41-,42+/m1/s1
    Key: RDECBWLKMPEKPM-PSCJHHPTSA-N
  • A: O([C@H]1C[C@]2([C@]3([C@]([C@]4(C(=C3)C(=O)[C@H](C)[C@@H](O[C@@H]5O[C@H](C)[C@@H](N(C)C)CC5)CCC[C@H](CC)OC(=O)C4)[H])(C=C[C@@]2(C1)[H])[H])[H])[H])[C@H]6[C@H](OC)[C@H](OC)[C@@H](OC)[C@H](C)O6
  • D: CC1=C[C@@]2([C@]([C@]3([C@]1(C[C@@H](O[C@H]4[C@H](OC)[C@H](OC)[C@@H](OC)[C@H](C)O4)C3)[H])[H])(C=C5[C@]2(CC(=O)O[C@@H](CC)CCC[C@H](O[C@@H]6O[C@H](C)[C@@H](N(C)C)CC6)[C@@H](C)C5=O)[H])[H])[H]
Properties
C41H65NO10 (A)
C42H67NO10 (D)
Molar mass 731.968 g·mol−1 (A)
745.995 g·mol−1 (D)
Pharmacology
QP53BX03 (WHO)
Topical, by mouth
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Spinosad
Clinical data
AHFS/Drugs.comMonograph
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CompTox Dashboard (EPA)
ECHA InfoCard100.103.254 Edit this at Wikidata

Spinosad is an insecticide based on chemical compounds found in the bacterial species Saccharopolyspora spinosa. The genus Saccharopolyspora was discovered in 1985 in isolates from crushed sugarcane. The bacteria produce yellowish-pink aerial hyphae, with bead-like chains of spores enclosed in a characteristic hairy sheath.[4] This genus is defined as aerobic, Gram-positive, nonacid-fast actinomycetes with fragmenting substrate mycelium. S. spinosa was isolated from soil collected inside a nonoperational sugar mill rum still in the Virgin Islands. Spinosad is a mixture of chemical compounds in the spinosyn family that has a generalized structure consisting of a unique tetracyclic ring system attached to an amino sugar (D-forosamine) and a neutral sugar (tri-Ο-methyl-L-rhamnose).[5] Spinosad is relatively nonpolar and not easily dissolved in water.[6]

Spinosad is a novel mode-of-action insecticide derived from a family of natural products obtained by fermentation of S. spinosa. Spinosyns occur in over 20 natural forms, and over 200 synthetic forms (spinosoids) have been produced in the lab.[7] Spinosad contains a mix of two spinosoids, spinosyn A, the major component, and spinosyn D (the minor component), in a roughly 17:3 ratio.[4]

Mode of action

Spinosad is highly active, by both contact and ingestion, in numerous insect species.[8] Its overall protective effect varies with insect species and life stage. It affects certain species only in the adult stage, but can affect other species at more than one life stage. The species subject to very high rates of mortality as larvae, but not as adults, may gradually be controlled through sustained larval mortality.[8] The mode of action of spinosoid insecticides is by a neural mechanism.[9] The spinosyns and spinosoids have a novel mode of action, primarily targeting binding sites on nicotinic acetylcholine receptors (nAChRs) of the insect nervous system that are distinct from those at which other insecticides have their activity. Spinosoid binding leads to disruption of acetylcholine neurotransmission.[5] Spinosad also has secondary effects as a γ-amino-butyric acid (GABA) neurotransmitter agonist.[5] It kills insects by hyperexcitation of the insect nervous system.[5] Spinosad has proven not to cause cross-resistance to any other known insecticide.[10]

Uses

Spinosad has been used around the world for the control of a variety of insect pests, including Lepidoptera, Diptera, Thysanoptera, Coleoptera, Orthoptera, and Hymenoptera, and many others.[11] It was first registered as a pesticide in the United States for use on crops in 1997.[11] Its labeled use rate is set at 1 ppm (1 mg a.i./kg of grain) and its maximum residue limit (MRL) or tolerance is set at 1.5 ppm. Spinosad's widespread commercial launch was deferred, awaiting final MRL or tolerance approvals in a few remaining grain-importing countries. It is considered a natural product, thus is approved for use in organic agriculture by numerous nations.[8] Two other uses for spinosad are for pets and humans. Spinosad has been used in oral preparations (as Comfortis) to treat C. felis, the cat flea, in canines and felines; the optimal dose set for canines is reported to be 30 mg/kg.[5]

Spinosad is sold under the brand names, Comfortis, Trifexis, and Natroba.[12][13] Trifexis also includes milbemycin oxime. Comfortis and Trifexis brands treat adult fleas on pets; the latter also prevents heartworm disease. Natroba is sold for treatment of human head lice. Spinosad is also commonly used to kill thrips.[14][15][16]

Comfortis and Trifexis were withdrawn in the European Union.[17][18]

Spinosyn A

Spinosyn A does not appear to interact directly with known insecticidal-relevant target sites, but rather acts via a novel mechanism.[9] Spinosyn A resembles a GABA antagonist and is comparable to the effect of avermectin on insect neurons.[7] Spinosyn A is highly active against neonate larvae of the tobacco budworm, Heliothis virescens, and is slightly more biologically active than spinosyn D. In general, spinosyns possessing a methyl group at C6 (spinosyn D-related analogs) tend to be more active and less affected by changes in the rest of the molecule.[10] Spinosyn A is slow to penetrate to the internal fluids of larvae; it is also poorly metabolized once it enters the insect.[10] The apparent lack of spinosyn A metabolism may contribute to its high level of activity, and may compensate for the slow rate of penetration.[10]

Resistance

Spinosad resistance has been found in Musca domestica,[19][20] Plutella xylostella,[21][20] Bactrocera dorsalis,[22][20] Frankliniella occidentalis,[23][20] and Cydia pomonella.[24][25][20]

Safety and ecotoxicology

Spinosad has high efficacy, a broad insect pest spectrum, low mammalian toxicity, and a good environmental profile, a unique feature of the insecticide compared to others currently used for the protection of grain products.[8] It is regarded as natural product-based, and approved for use in organic agriculture by numerous national and international certifications.[11] Spinosad residues are highly stable on grains stored in bins, with protection ranging from 6 months to 2 years.[8][clarification needed] Ecotoxicology parameters have been reported for spinosad, and are:[26]

Chronic exposure studies failed to induce tumor formation in rats and mice; mice given up to 51 mg/kg/day for 18 months resulted in no tumor formation.[27] Similarly, administration of 25 mg/kg/day to rats for 24 months did not result in tumor formation.[28]

References

  1. ^ "Natroba- spinosad suspension". DailyMed. U.S. National Library of Medicine. 28 April 2021. Retrieved 1 July 2023.
  2. ^ "Spinosad suspension". DailyMed. U.S. National Library of Medicine. 31 May 2023. Retrieved 1 July 2023.
  3. ^ "Comfortis- spinosad tablet, chewable". DailyMed. U.S. National Library of Medicine. 1 July 2021. Retrieved 1 July 2023.
  4. ^ a b Mertz F, Yao RC (January 1990). "Saccharopolyspora spinosa sp. nov. Isolated from soil Collected in a Sugar Mill Rum Still". International Journal of Systematic Bacteriology. 40 (1): 34–39. doi:10.1099/00207713-40-1-34.
  5. ^ a b c d e Snyder DE, Meyer J, Zimmermann AG, Qiao M, Gissendanner SJ, Cruthers LR, et al. (December 2007). "Preliminary studies on the effectiveness of the novel pulicide, spinosad, for the treatment and control of fleas on dogs". Veterinary Parasitology. 150 (4): 345–351. doi:10.1016/j.vetpar.2007.09.011. PMID 17980490.
  6. ^ Crouse GD, Sparks TC, Schoonover J, Gifford J, Dripps J, Bruce T, et al. (February 2001). "Recent advances in the chemistry of spinosyns". Pest Management Science. 57 (2): 177–185. doi:10.1002/1526-4998(200102)57:2<177::AID-PS281>3.0.CO;2-Z. PMID 11455648.
  7. ^ a b Watson G (31 May 2001). "Actions of Insecticidal Spinosyns on γ-Aminobutyric Acid Responses for Small-Diameter Cockroach Neurons". Pesticide Biochemistry and Physiology. 71: 20–28. doi:10.1006/pest.2001.2559.
  8. ^ a b c d e Hertlein M, Thompson GD, Subramanyam B, Athanassiou CG (12 January 2011). "Spinosad: A new natural product for stored grain protection". Stored Products. 47 (3): 131–146. doi:10.1016/j.jspr.2011.01.004.
  9. ^ a b Orr N, Shaffner AJ, Richey K, Crouse GD (30 April 2009). "Novel mode of action of spinosad: Receptor binding studies demonstrating lack of interaction with known insecticidal target sites". Pesticide Biochemistry and Physiology. 95: 1–5. doi:10.1016/j.pestbp.2009.04.009.
  10. ^ a b c d Sparks TC, Crouse GD, Durst G (October 2001). "Natural products as insecticides: the biology, biochemistry and quantitative structure-activity relationships of spinosyns and spinosoids". Pest Management Science. 57 (10): 896–905. doi:10.1002/ps.358. PMID 11695182.
  11. ^ a b c Sparks T, Dripps JE, Watson GB, Paroonagian D (6 November 2012). "Resistance and cross-resistance to the spinosyns- A review and analysis". Pesticide Biochemistry and Physiology. 102: 1–10. doi:10.1016/j.pestbp.2011.11.004. Retrieved 17 November 2011.
  12. ^ "Spinosad international brands". Drugs.com. 3 January 2020. Retrieved 30 January 2020.
  13. ^ "Spinosad US brands". Drugs.com. 3 January 2020. Retrieved 30 January 2020.
  14. ^ "Spinosad - brand name list from". Drugs.com. Retrieved 20 October 2012.
  15. ^ Bethke JA, Dreistadt SH, Varela LG, Phillips PA, O'Donnell CA (May 2014). Thripsm (PDF). University of California Statewide Integrated Pest Management Program. UCANR Publication. (Report). Integrated Pest Management for Home Gardeners and Landscape Professionals.
  16. ^ Merchant M. "Safer Flea Control | Insects in the City". Texas A&M AgriLife Extension Service. Retrieved 20 October 2012.
  17. ^ "Comfortis EPAR". European Medicines Agency. 26 June 2023. Retrieved 3 July 2023.
  18. ^ "Trifexis EPAR". European Medicines Agency. 5 November 2020. Retrieved 3 July 2023.
  19. ^ Liu N, Yue X (August 2000). "Insecticide resistance and cross-resistance in the house fly (Diptera: Muscidae)". Journal of Economic Entomology. 93 (4): 1269–1275. doi:10.1603/0022-0493-93.4.1269. PMID 10985042. S2CID 26611971.
  20. ^ a b c d e Biondi A, Mommaerts V, Smagghe G, Viñuela E, Zappalà L, Desneux N (December 2012). "The non-target impact of spinosyns on beneficial arthropods". Pest Management Science. Society of Chemical Industry (Wiley). 68 (12): 1523–1536. doi:10.1002/ps.3396. PMID 23109262.
  21. ^ Sayyed AH, Omar D, Wright DJ (August 2004). "Genetics of spinosad resistance in a multi-resistant field-selected population of Plutella xylostella". Pest Management Science. 60 (8): 827–832. doi:10.1002/ps.869. PMID 15307676.
  22. ^ Hsu JC, Feng HT (June 2006). "Development of resistance to spinosad in oriental fruit fly (Diptera: Tephritidae) in laboratory selection and cross-resistance" (PDF). Journal of Economic Entomology. 99 (3): 931–936. doi:10.1603/0022-0493-99.3.931. PMID 16813333. S2CID 182038998.
  23. ^ Bielza P, Quinto V, Fernandez E, Grávalos C, Contreras J (June 2007). "Genetics of spinosad resistance in Frankliniella occidentalis (Thysanoptera: Thripidae)". Journal of Economic Entomology. 100 (3): 916–920. doi:10.1603/0022-0493(2007)100[916:gosrif]2.0.co;2 (inactive 25 January 2024). PMID 17598556. S2CID 25560262.((cite journal)): CS1 maint: DOI inactive as of January 2024 (link)
  24. ^ Reyes M, Franck P, Charmillot PJ, Ioriatti C, Olivares J, Pasqualini E, Sauphanor B (September 2007). "Diversity of insecticide resistance mechanisms and spectrum in European populations of the codling moth, Cydia pomonella". Pest Management Science. 63 (9): 890–902. doi:10.1002/ps.1421. PMID 17665366.
  25. ^ See for continued updates: Mota-Sanchez D, Wise JC, et al. (Insecticide Resistance Action Committee). "Arthropod Pesticide Resistance Database". Michigan State University.
  26. ^ Brunner JF. "Codling Moth and Leafroller Control Using Chemicals" (PDF). Tree Fruit Research and Extension Center. Washington State University. Archived from the original (PDF) on 3 August 2003. Retrieved 20 October 2012.
  27. ^ Stebbins KE, Bond DM, Novilla MN, Reasor MJ (February 2002). "Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in CD-1 mice". Toxicological Sciences. 65 (2): 276–287. doi:10.1093/toxsci/65.2.276. PMID 11812932.
  28. ^ Yano BL, Bond DM, Novilla MN, McFadden LG, Reasor MJ (February 2002). "Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in Fischer 344 rats". Toxicological Sciences. 65 (2): 288–298. doi:10.1093/toxsci/65.2.288. PMID 11812933.

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