Avermectin

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The avermectins are a series 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties.[1][2] These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis, a soil actinomycete. Eight different avermectins were isolated in 4 pairs of homologue compounds, with a major (a-component) and minor (b-component) component usually in ratios of 80:20 to 90:10.[2] Other anthelmintics derived from the avermectins include ivermectin, selamectin, doramectin and abamectin.

Avermectins

History[edit]

In 1978, an actinomycete was isolated at The Kitasato Institute from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan. Later that year, the isolated actinomycete was sent to Merck Sharp and Dohme Research Laboratories for testing. Various, carefully controlled broths were fermented using the isolated actinomycete. Early tests indicated that some of the whole, fermented broths were active against Nematospiroides dubius in mice over at least an eightfold range without notable toxicity. Subsequent to this, the anthelmintic activity was isolated and identified as a family of closely related compounds. The family of compounds were finally characterized and the novel species that produced them were described by a team at Merck in 1978.[3]

In 2002, Yoko Takahashi and others at the Kitasato Institute for Life Sciences, Kitasato University and at The Kitasato Institute, proposed that Streptomyces avermitilis be renamed Streptomyces avermectinius.[4]

Avermectin therapy for rodent fur mite infestation[edit]

A commonly used therapy in recent times has been based on oral, parenteral, topical, or spot topical (as in veterinary flea repellant "drops") administration of avermectins. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 microgram/kg or less (200 micrograms / kg ivermectin appearing to be the common interspecies standard, from humans to horses to housepets, unless otherwise indicated). Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activities.[5]

CAUTION: As such veterinary preparations are generally widely available without prescription, cheap (<$1 per 100 kg weight of subject treated in cattle or equine generic formulations), and commonly dispensed in fluid or paste form for adjustable dosage, non-professional end users should take care to notice that doses are in MICROgrams per kg (1/1000th of a milligram or 1/ 1,000,000th of a gram) and re-check any computations when administering to smaller or juvenile animals, especially when using directions found online. Typos, the lack of an easy way to type the SI designation for micro-, and easily overlooked decimal points when expressing in miligrams (200 micrograms = 0.2 mg, often expressed as .2 mg) creates much potential for error or misreading. If unsure and whenever possible, leave administration to a veterinary professional.

Mechanism of action[edit]

The avermectins block the transmittance of electrical activity in invertebrate nerve and muscle cells mostly by enhancing the effects of glutamate at the invertebrate-specific glutamate-gated chloride channel, with minor effects on gamma-aminobutyric acid (GABA) receptors.[6][7][8] This causes an influx of chloride ions into the cells, leading to hyperpolarisation and subsequent paralysis of invertebrate neuromuscular systems; comparable doses are not toxic for mammals because they do not possess glutamate-gated chloride channels.[9]

Toxicity and side-effects[edit]

Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation.[10] Research on ivermectin, piperazine, and dichlorvos in combinations also shows potential for toxicity.[11] Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, nitric oxide, prostaglandin E2, and increase of intracellular concentration of Ca2+.[12] Adverse effects are usually transient; severe effects are rare and probably occur only with substantial overdose, but include coma, hypotension, and respiratory failure, which can lead to death. No specific therapy exists, but symptomatic management usually leads to a favorable prognosis.[13]

Avermectin biosynthesis[edit]

Diagram showing the schematic synthesis of avermectins.

The gene cluster for biosynthesis of avermectin from Streptomyces avermitilis has been sequenced.[14] The avermectin biosynthesis gene cluster encodes enzymes responsible for four steps of avermectin production: 1) production of the avermectin aglycon by polyketide synthases (PKS), 2) modification of the aglycon, 3) synthesis of modified sugars and 4) glycosylation of the modified avermectin aglycon. This gene cluster can produce eight avermectins which have minor structural differences.[15]

Organization of the Avermectin Polyketide Synthase

The avermectin initial aglycon is synthesized by the polyketide synthase activity of four proteins (AVES 1, AVES 2, AVES 3, and AVES 4). The activity of this enzyme complex is similar to type I polyketide synthases.[15] Either 2-methylbutyrl CoA or isobutyrl CoA can be used as starting units and are extended by seven acetate units and 5 propionate units to produce avermectin “a” series or “b” series, respectively.[15] The initial aglycon is subsequently released from the thioesterase domain of AVES 4 by formation of an intramolecular cyclic ester.

The avermectin initial aglycon is further modified by other enzymes in the avermectin biosynthetic gene cluster. AveE has cytochrome P450 monooxygenase activity and facilitates the furan ring formation between C6 and C8.[15] AveF has NAD(P)H-dependent ketoreductase activity which reduces the C5 keto group to a hydroxyl.[15] AveC influences the dehydratase activity in module two (affecting C22-C23) although the mechanism by which it does this is not clear.[14][15] AveD has SAM-dependant C5 O-methyltransferase activity.[15] Whether AveC or AveD act on the aglycon determines whether the resulting avermectin aglycon will produce avermectin series “A” or “B” and series 1 or 2, respectively.

There are nine open reading frames (orf1 and aveBI-BVIII) downstream of aveA4 which are known involved with glycosylation and sugar synthesis.[15] AveBII-BVIII are responsible for synthesis of dTDP-L-oleandrose and AveBI is responsible for glycosylation of the avermectin aglycon with the dTDP-sugar.[15] The sequence of orf1 suggests that its product will have reductase activity, but this functionality does not appear to be necessary for avermectin synthesis.[15]

Other uses[edit]

Abamectin is the active ingredient in some commercial ant bait traps.

See also[edit]

  • Milbemycins are a chemically closely related group of parasiticides.
  • Avermectin/ivermection glycorandomization has led to a range of new differentially-glycosylated analogs.[16]

References[edit]

  1. ^ Ōmura, Satoshi; Shiomi, Kazuro (2007). "Discovery, chemistry, and chemical biology of microbial products". Pure and Applied Chemistry 79 (4). doi:10.1351/pac200779040581. 
  2. ^ a b Pitterna, Thomas; Cassayre, Jérôme; Hüter, Ottmar Franz; Jung, Pierre M.J.; Maienfisch, Peter; Kessabi, Fiona Murphy; Quaranta, Laura; Tobler, Hans (2009). "New ventures in the chemistry of avermectins". Bioorganic & Medicinal Chemistry 17 (12): 4085. doi:10.1016/j.bmc.2008.12.069. 
  3. ^ Burg, R. W.; Miller, B. M.; Baker, E. E.; Birnbaum, J.; Currie, S. A.; Hartman, R.; Kong, Y.-L.; Monaghan, R. L.; Olson, G.; Putter, I.; Tunac, J. B.; Wallick, H.; Stapley, E. O.; Oiwa, R.; Omura, S. (1979). "Avermectins, New Family of Potent Anthelmintic Agents: Producing Organism and Fermentation". Antimicrobial Agents and Chemotherapy 15 (3): 361. doi:10.1128/AAC.15.3.361. PMID 464561. 
  4. ^ Takahashi, Y. (2002). "Streptomyces avermectinius sp. nov., an avermectin-producing strain". International Journal of Systematic and Evolutionary Microbiology 52 (6): 2163. doi:10.1099/ijs.0.02237-0. 
  5. ^ Hotson, I. K. (1982). "The avermectins: A new family of antiparasitic agents". Journal of the South African Veterinary Association 53 (2): 87–90. PMID 6750121. 
  6. ^ Cully, Doris F.; Vassilatis, Demetrios K.; Liu, Ken K.; Paress, Philip S.; Van Der Ploeg, Lex H. T.; Schaeffer, James M.; Arena, Joseph P. (1994). "Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans". Nature 371 (6499): 707. Bibcode:1994Natur.371..707C. doi:10.1038/371707a0. PMID 7935817. 
  7. ^ Bloomquist, Jeffrey R. (1996). "Ion Channels as Targets for Insecticides". Annual Review of Entomology 41: 163–90. doi:10.1146/annurev.en.41.010196.001115. PMID 8546445. 
  8. ^ Bloomquist, Jeffrey R. (2003). "Chloride channels as tools for developing selective insecticides". Archives of Insect Biochemistry and Physiology 54 (4): 145–56. doi:10.1002/arch.10112. PMID 14635176. 
  9. ^ Bloomquist, Jeffrey R. (1993). "Toxicology, mode of action and target site-mediated resistance to insecticides acting on chloride channels". Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology 106 (2): 301. doi:10.1016/0742-8413(93)90138-b. 
  10. ^ Clark, J K; Scott, J G; Campos, F; Bloomquist, J R (1995). "Resistance to Avermectins: Extent, Mechanisms, and Management Implications". Annual Review of Entomology 40: 1–30. doi:10.1146/annurev.en.40.010195.000245. PMID 7810984. 
  11. ^ Toth, L. A.; Oberbeck, C; Straign, C. M.; Frazier, S; Rehg, J. E. (2000). "Toxicity evaluation of prophylactic treatments for mites and pinworms in mice". Contemporary topics in laboratory animal science / American Association for Laboratory Animal Science 39 (2): 18–21. PMID 11487234. 
  12. ^ Viktorov, A. V.; Yurkiv, V. A. (2003). "Effect of ivermectin on function of liver macrophages". Bulletin of experimental biology and medicine 136 (6): 569–71. PMID 15500074. 
  13. ^ Yang, Chen-Chang (2012). "Acute Human Toxicity of Macrocyclic Lactones". Current Pharmaceutical Biotechnology 13 (6): 999–1003. doi:10.2174/138920112800399059. PMID 22039794. 
  14. ^ a b Ikeda, H.; Nonomiya, T.; Usami, M.; Ohta, T.; Omura, S. (1999). "Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis". Proceedings of the National Academy of Sciences 96 (17): 9509. Bibcode:1999PNAS...96.9509I. doi:10.1073/pnas.96.17.9509. 
  15. ^ a b c d e f g h i j Yoon, Y. J.; Kim, E.-S.; Hwang, Y.-S.; Choi, C.-Y. (2004). "Avermectin: Biochemical and molecular basis of its biosynthesis and regulation". Applied Microbiology and Biotechnology 63 (6): 626. doi:10.1007/s00253-003-1491-4. PMID 14689246. 
  16. ^ Zhang, Changsheng; Albermann, Christoph; Fu, Xun; Thorson, Jon S. (2006). "The in Vitro Characterization of the Iterative Avermectin Glycosyltransferase AveBI Reveals Reaction Reversibility and Sugar Nucleotide Flexibility". Journal of the American Chemical Society 128 (51): 16420. doi:10.1021/ja065950k. PMID 17177349.