Avermectin

Last updated
Skeletal structure of the 8 different natural avermectins Avermectins skeletal.svg
Skeletal structure of the 8 different natural avermectins

The avermectins are a group of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties. [2] [3] These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis , a soil actinomycete. Eight different avermectins were isolated in four pairs of homologue compounds (A1, A2, B1, B2), with a major (a-component) and minor (b-component) component usually in ratios of 80:20 to 90:10. [3] Avermectin B1, a mixture of B1a and B1b, is the drug and pesticide abamectin. Other anthelmintics derived from the avermectins include ivermectin, selamectin, doramectin, eprinomectin.

Contents

Half of the 2015 Nobel Prize in Physiology or Medicine was awarded to William C. Campbell and Satoshi Ōmura for discovering avermectin, [4] "the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases."

History

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 eight-fold range without notable toxicity. Subsequent to this, the anthelmintic activity was isolated and identified as a family of closely related compounds. The compounds were finally characterized and the novel species that produced them were described by a team at Merck in 1978, and named Streptomyces avermitilis (with the adjective probably intended to mean that it kills worms). [5]

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. [6]

Dosing

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 μg/kg or less (200 μg/kg ivermectin appearing to be the common interspecies standard, from humans to horses to house pets, unless otherwise indicated).[ citation needed ] Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activities. [7]

Mechanism of action

The avermectins block the transmission of electrical activity in invertebrate nerve and muscle cells mostly by enhancing the effects of glutamate at the glutamate-gated chloride channel that is specific to protostome invertebrates, [8] with minor effects on gamma-aminobutyric acid receptors. [9] [10] [11] 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 protostome-specific glutamate-gated chloride channels. [12] [ dubious – discuss ] [8] Together with the milbemycins, avermectins belong to IRAC group 6. [13]

Toxicity and side effects

Resistance to avermectins has been reported, which suggests moderation in use. [14] Resistance in Caenorhabditis elegans has been observed by the most obvious route – variation of the glutamate-gated chloride channel. [15] [16] Research on ivermectin, piperazine, and dichlorvos in combinations also shows potential for toxicity. [17] Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, nitric oxide, prostaglandin E2, and increase of intracellular concentration of Ca2+. [18] 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. [19] [20]

Avermectin biosynthesis

Diagram showing the schematic synthesis of avermectins Avermectin Biosynthesis Pathway.png
Diagram showing the schematic synthesis of avermectins

The gene cluster for biosynthesis of avermectin from S. avermitilis has been sequenced. [21] The avermectin biosynthesis gene cluster encodes enzymes responsible for four steps of avermectin production: 1) production of the avermectin aglycon by polyketide synthases, 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. [1]

Organization of the avermectin polyketide synthase Avermectin PKS.png
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. [1] Either 2-methylbutyryl CoA or isobutyryl CoA can be used as starting units and are extended by seven acetate units and five propionate units to produce avermectin “a” series or “b” series, respectively. [1] The initial aglycon is subsequently released from the thioesterase domain of AVES 4 by formation of an intramolecular cyclic ester. [1]

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. [1] AveF has NAD(P)H-dependent ketoreductase activity which reduces the C5 keto group to a hydroxyl. [1] AveC influences the dehydratase activity in module two (affecting C22-C23), although the mechanism by which it does this is not clear. [21] [1] AveD has SAM-dependent C5 O-methyltransferase activity. [1] Whether AveC or AveD acts on the aglycon determines whether the resulting avermectin aglycon will produce avermectin, series “A” or “B” and series 1 or 2 (see synthesis schematic diagram table), respectively. [1]

Nine open reading frames (orf1 and aveBI-BVIII) are downstream of aveA4, which are known involved with glycosylation and sugar synthesis. [1] AveBII-BVIII are responsible for synthesis of dTDP-L-oleandrose and AveBI is responsible for glycosylation of the avermectin aglycon with the dTDP-sugar. [1] The sequence of orf1 suggests that its product will have reductase activity, but this functionality does not appear to be necessary for avermectin synthesis. [1]

Other uses

Abamectin is the active ingredient in some commercial ant bait traps. Ivermectin, formulated from Avermectin, has a wide variety of uses in human beings. According to a paper (Ivermectin: “Wonder Drug” from Japan: the human use perspective) written by the drugs co-creator Satoshi Ōmura and Andy Crump for The Japan Academy, Ivermectin has improved the lives of billions of people worldwide and not solely for uses as an anti parasitic. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Onchocerciasis</span> Human helminthiasis (infection by parasite)

Onchocerciasis, also known as river blindness, is a disease caused by infection with the parasitic worm Onchocerca volvulus. Symptoms include severe itching, bumps under the skin, and blindness. It is the second-most common cause of blindness due to infection, after trachoma.

<span class="mw-page-title-main">Abamectin</span> Insecticide and anti-parasitic worm chemical

Abamectin (also called avermectin B1) is a widely used insecticide and anthelmintic. Abamectin, is a member of the avermectin family and is a natural fermentation product of soil dwelling actinomycete Streptomyces avermitilis. Abamectin differs from ivermectin, the popular member of the avermectin family, by a double bond between carbons 22 and 25. Fermentation of Streptomyces avermitilis yields eight closely related avermectin homologs, with the B1a and B1b forms comprising the majority of the fermentation. The non-proprietary name, abamectin, refers to a mixture of B1a (~80%) and B1b (~20%). Out of all the avermectins, abamectin is the only one that is used both in agriculture and pharmaceuticals.

<i>Streptomyces</i> Genus of bacteria

Streptomyces is the largest genus of Actinomycetota, and the type genus of the family Streptomycetaceae. Over 700 species of Streptomyces bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, and have very large genomes with high GC content. Found predominantly in soil and decaying vegetation, most streptomycetes produce spores, and are noted for their distinct "earthy" odor that results from production of a volatile metabolite, geosmin. Different strains of the same species may colonize very diverse environments.

In organic chemistry, polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone and methylene groups: [−C(=O)−CH2−]n. First studied in the early 20th century, discovery, biosynthesis, and application of polyketides has evolved. It is a large and diverse group of secondary metabolites caused by its complex biosynthesis which resembles that of fatty acid synthesis. Because of this diversity, polyketides can have various medicinal, agricultural, and industrial applications. Many polyketides are medicinal or exhibit acute toxicity. Biotechnology has enabled discovery of more naturally-occurring polyketides and evolution of new polyketides with novel or improved bioactivity.

<span class="mw-page-title-main">Ivermectin</span> Medication for parasite infestations

Ivermectin is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, it is used to treat infestations including head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis and lymphatic filariasis. It works through many mechanisms to kill the targeted parasites, and can be taken by mouth, or applied to the skin for external infestations. It belongs to the avermectin family of medications.

<span class="mw-page-title-main">Selamectin</span> Topical parasiticide for dogs and cats

Selamectin, sold under the brand name Revolution, among others, is a topical parasiticide and anthelminthic used on dogs and cats. It treats and prevents infections of heartworms, fleas, ear mites, sarcoptic mange (scabies), and certain types of ticks in dogs, and prevents heartworms, fleas, ear mites, hookworms, and roundworms in cats. It is structurally related to ivermectin and milbemycin. Selamectin is not approved for human use.

<span class="mw-page-title-main">Moxidectin</span> Chemical compound

Moxidectin is an anthelmintic drug used in animals to prevent or control parasitic worms (helminths), such as heartworm and intestinal worms, in dogs, cats, horses, cattle, sheep and wombats. Moxidectin kills some of the most common internal and external parasites by selectively binding to a parasite's glutamate-gated chloride ion channels. These channels are vital to the function of invertebrate nerve and muscle cells; when moxidectin binds to the channels, it disrupts neurotransmission, resulting in paralysis and death of the parasite.

The milbemycins are a group of macrolides chemically related to the avermectins and were first isolated in 1972 from Streptomyces hygroscopicus. They are used in veterinary medicine as antiparasitic agents against worms, ticks and fleas. They also show insecticidal and acaricidal activity.

<span class="mw-page-title-main">Milbemycin oxime</span> Chemical compound

Milbemycin oxime, sold under the brand name Interceptor among others, is a veterinary medication from the group of milbemycins, used as a broad spectrum antiparasitic. It is active against worms (anthelmintic) and mites (miticide).

<span class="mw-page-title-main">Anthelmintic</span> Antiparasitic drugs that expel parasitic worms (helminths) from the body

Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. They may also be called vermifuges or vermicides. Anthelmintics are used to treat people who are infected by helminths, a condition called helminthiasis. These drugs are also used to treat infected animals, particularly small ruminants such as goats and sheep.

<span class="mw-page-title-main">Emamectin</span> Chemical compound

Emamectin is the 4″-deoxy-4″-methylamino derivative of abamectin, a 16-membered macrocyclic lactone produced by the fermentation of the soil actinomycete Streptomyces avermitilis. It is generally prepared as the salt with benzoic acid, emamectin benzoate, which is a white or faintly yellow powder. Emamectin is widely used in the US and Canada as an insecticide because of its chloride channel activation properties.

<i>Streptomyces avermitilis</i> Species of bacterium

Streptomyces avermitilis is a species of bacteria in the genus Streptomyces. This bacterium was discovered by Satoshi Ōmura in Shizuoka Prefecture, Japan.

Streptomyces isolates have yielded the majority of human, animal, and agricultural antibiotics, as well as a number of fundamental chemotherapy medicines. Streptomyces is the largest antibiotic-producing genus of Actinomycetota, producing chemotherapy, antibacterial, antifungal, antiparasitic drugs, and immunosuppressants. Streptomyces isolates are typically initiated with the aerial hyphal formation from the mycelium.

<span class="mw-page-title-main">Satoshi Ōmura</span> Japanese biochemist, co-inventor of ivermectin (born 1935)

Satoshi Ōmura is a Japanese biochemist. He is known for the discovery and development of hundreds of pharmaceuticals originally occurring in microorganisms. In 2015, he was awarded the Nobel Prize in Physiology or Medicine jointly with William C. Campbell for their role in the discovery of avermectins and ivermectin. the world's first endectocide and a safe and highly effective microfilaricide. It is believed that the large molecular size of ivermectin prevents it from crossing the blood/aqueous humour barrier, and renders the drug an important treatment of helminthically-derived blindness.

<span class="mw-page-title-main">William C. Campbell (scientist)</span> Irish-American microbiologist and co-discoverer of avermectin (born 1930)

William Cecil Campbell is an Irish-American microbiologist known for his work in discovering a novel therapy against infections caused by roundworms, for which he was jointly awarded the 2015 Nobel Prize in Physiology or Medicine. He helped to discover a class of drugs called avermectins, whose derivatives have been shown to have "extraordinary efficacy" in treating River blindness and Lymphatic filariasis, among other parasitic diseases affecting animals and humans. Campbell worked at the Merck Institute for Therapeutic Research 1957–1990, and has become a research fellow emeritus at Drew University.

Chloride channel openers refer to a specific category of drugs designed to modulate chloride channels in the human body. Chloride channels are anion-selective channels which are involved in a wide variety of physiological functions and processes such as the regulation of neuroexcitation, transepithelial salt transport, and smooth muscle contraction. Due to their distribution throughout the body, diversity, functionality, and associated pathology, chloride channels represent an ideal target for the development of channel modulating drugs such as chloride channel openers.

Streptomyces caelestis is a bacterium species from the genus of Streptomyces which has been isolated from soil in Utah in the United States. Streptomyces caelestis produces desalicetin, isocelesticetin B, caelesticetin, citreamicin θ A, citreamicin θ B, citreaglycon A and dehydrocitreaglycon.

<span class="mw-page-title-main">Glutamate (neurotransmitter)</span> Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

Streptomyces microflavus is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces microflavus produces nemadectin, fattiviracin A1, milbemycin and deoxyuridines. Streptomyces microflavus also produces the ionophore valinomycin. Streptomyces microflavus is also known to cause potato common scab disease in Korea.

<span class="mw-page-title-main">Tetracenomycin C</span> Chemical compound

Tetracenomycin C is an antitumor anthracycline-like antibiotic produced by Streptomyces glaucescens GLA.0. The pale-yellow antibiotic is active against some gram-positive bacteria, especially against streptomycetes. Gram-negative bacteria and fungi are not inhibited. In considering the differences of biological activity and the functional groups of the molecule, tetracenomycin C is not a member of the tetracycline or anthracyclinone group of antibiotics. Tetracenomycin C is notable for its broad activity against actinomycetes. As in other anthracycline antibiotics, the framework is synthesized by a polyketide synthase and subsequently modified by other enzymes.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 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): 626–34. doi:10.1007/s00253-003-1491-4. PMID   14689246. S2CID   2578270.
  2. ↑ Ōmura, Satoshi; Shiomi, Kazuro (2007). "Discovery, chemistry, and chemical biology of microbial products". Pure and Applied Chemistry. 79 (4): 581–591. doi: 10.1351/pac200779040581 .
  3. 1 2 Jeschke, Peter; Witschel, Matthias; Krämer, Wolfgang; Schirmer, Ulrich (25 January 2019). "33.6 Glutamate‐gated Chloride Channel Allosteric Modulators: Avermectins and Milbemycins". Modern Crop Protection Compounds (3rd ed.). Wiley‐VCH. pp. 1478–1500. ISBN   9783527699261.{{cite book}}: CS1 maint: date and year (link)
  4. ↑ "The Nobel Prize in Physiology or Medicine 2015". Nobel Prize . 2020-12-03. Retrieved 2020-12-03.
  5. ↑ 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): 361–7. doi:10.1128/AAC.15.3.361. PMC   352666 . PMID   464561.
  6. ↑ Takahashi, Y. (2002). "Streptomyces avermectinius sp. nov., an avermectin-producing strain". International Journal of Systematic and Evolutionary Microbiology. 52 (6): 2163–8. doi:10.1099/00207713-52-6-2163. PMID   12508884.
  7. ↑ 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.
  8. 1 2 Wolstenholme, Adrian J. (2012-10-04). "Glutamate-gated Chloride Channels". Journal of Biological Chemistry . 287 (48). American Society for Biochemistry & Molecular Biology (ASBMB): 40232–40238. doi: 10.1074/jbc.r112.406280 . ISSN   0021-9258. PMC   3504739 . PMID   23038250.
  9. ↑ 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): 707–11. Bibcode:1994Natur.371..707C. doi:10.1038/371707a0. PMID   7935817. S2CID   4337014.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Bloomquist, Jeffrey R. (1993). "Toxicology, mode of action and target site-mediated resistance to insecticides acting on chloride channels". Comparative Biochemistry and Physiology C. 106 (2): 301–314. doi:10.1016/0742-8413(93)90138-b. PMID   7904908.
  13. ↑ Sparks, Thomas C; Storer, Nicholas; Porter, Alan; Slater, Russell; Nauen, Ralf (2021). "Insecticide resistance management and industry: the origins and evolution of the I nsecticide R esistance A ction C ommittee (IRAC) and the mode of action classification scheme". Pest Management Science. 77 (6): 2609–2619. doi: 10.1002/ps.6254 . ISSN   1526-498X. PMC   8248193 . PMID   33421293.
  14. ↑ 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). Annual Reviews: 1–30. doi:10.1146/annurev.en.40.010195.000245. ISSN   0066-4170. PMID   7810984.
  15. ↑ Ghosh, R.; Andersen, E. C.; Shapiro, J. A.; Gerke, J. P.; Kruglyak, L. (2012-02-02). "Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in C. elegans". Science . 335 (6068). American Association for the Advancement of Science (AAAS): 574–578. Bibcode:2012Sci...335..574G. doi:10.1126/science.1214318. ISSN   0036-8075. PMC   3273849 . PMID   22301316.
  16. ↑ Horoszok, Lucy; Raymond, Valérie; Sattelle, David B; Wolstenholme, Adrian J (2001). "GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans". British Journal of Pharmacology . 132 (6). Wiley: 1247–1254. doi: 10.1038/sj.bjp.0703937 . ISSN   0007-1188. PMC   1572670 . PMID   11250875.
  17. ↑ 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. 39 (2): 18–21. PMID   11487234.
  18. ↑ 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. doi:10.1023/b:bebm.0000020206.23474.e9. PMID   15500074. S2CID   851108.
  19. ↑ Yang, Chen-Chang (2012). "Acute Human Toxicity of Macrocyclic Lactones". Current Pharmaceutical Biotechnology. 13 (6): 999–1003. doi:10.2174/138920112800399059. PMID   22039794.
  20. ↑ Peter, John. "Ivermectin".
  21. 1 2 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): 9509–9514. Bibcode:1999PNAS...96.9509I. doi: 10.1073/pnas.96.17.9509 . PMC   22239 . PMID   10449723.
  22. ↑ Crump, Andy; Ōmura, Satoshi (2011). "Ivermectin, 'wonder drug' from Japan: the human use perspective". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. 87 (2): 13–28. Bibcode:2011PJAB...87...13C. doi: 10.2183/pjab.87.13 . PMC   3043740 . PMID   21321478.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.