{{Short description|Drugs to treat parasitic worms and insect pests}} {{distinguish|ivermectin}} thumb|right|300px|Skeletal structure of the 8 different natural avermectins<ref name="YoonKim2004" /> The '''avermectins''' are a group of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties.<ref>{{cite journal |doi=10.1351/pac200779040581|title=Discovery, chemistry, and chemical biology of microbial products|journal=Pure and Applied Chemistry|volume=79|issue=4|pages=581–591|year=2007|last1=Ōmura|first1=Satoshi|last2=Shiomi|first2=Kazuro|doi-access=free}}</ref><ref name=":0">{{Cite book |last=Jeschke |first=Peter |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9783527699261 |title=Modern Crop Protection Compounds |last2=Witschel |first2=Matthias |last3=Krämer |first3=Wolfgang |last4=Schirmer |first4=Ulrich |date=25 January 2019 |publisher=Wiley‐VCH |isbn=9783527699261 |edition=3rd |pages=1478-1500 |chapter=33.6 Glutamate‐gated Chloride Channel Allosteric Modulators: Avermectins and Milbemycins}}</ref> 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.<ref name=":0" /> 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.

Half of the 2015 Nobel Prize in Physiology or Medicine was awarded to William C. Campbell and Satoshi Ōmura for discovering avermectin,<ref name="Nobel" /> "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).<ref>{{cite journal |doi=10.1128/AAC.15.3.361|pmid=464561|title=Avermectins, New Family of Potent Anthelmintic Agents: Producing Organism and Fermentation|journal=Antimicrobial Agents and Chemotherapy|volume=15|issue=3|pages=361–7|year=1979|last1=Burg|first1=R. W.|last2=Miller|first2=B. M.|last3=Baker|first3=E. E.|last4=Birnbaum|first4=J.|last5=Currie|first5=S. A.|last6=Hartman|first6=R.|last7=Kong|first7=Y.-L.|last8=Monaghan|first8=R. L.|last9=Olson|first9=G.|last10=Putter|first10=I.|last11=Tunac|first11=J. B.|last12=Wallick|first12=H.|last13=Stapley|first13=E. O.|last14=Oiwa|first14=R.|last15=Omura|first15=S.|pmc=352666}}</ref>

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''.<ref>{{cite journal |doi= 10.1099/00207713-52-6-2163|title= ''Streptomyces avermectinius'' sp. nov., an avermectin-producing strain|journal= International Journal of Systematic and Evolutionary Microbiology|volume= 52|issue= 6|pages= 2163–8|year= 2002|last1= Takahashi|first1= Y.|pmid=12508884}}</ref>

== 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&nbsp;μg/kg or less (200&nbsp;μg/kg ivermectin appearing to be the common interspecies standard, from humans to horses to house pets, unless otherwise indicated).{{citation needed|date=November 2020}} Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activities.<ref>{{cite journal |pmid=6750121|year=1982|last1=Hotson|first1=I. K.|title=The avermectins: A new family of antiparasitic agents|journal=Journal of the South African Veterinary Association|volume=53|issue=2|pages=87–90}}</ref>

== 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,<ref name="Wolstenholme-2012" /> with minor effects on gamma-aminobutyric acid receptors.<ref>{{cite journal |bibcode=1994Natur.371..707C|title=Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans|journal=Nature|volume=371|issue=6499|pages=707–11|last1=Cully|first1=Doris F.|last2=Vassilatis|first2=Demetrios K.|last3=Liu|first3=Ken K.|last4=Paress|first4=Philip S.|last5=Van Der Ploeg|first5=Lex H. T.|last6=Schaeffer|first6=James M.|last7=Arena|first7=Joseph P.|year=1994|doi=10.1038/371707a0|pmid=7935817|s2cid=4337014}} </ref><ref>{{cite journal |doi=10.1146/annurev.en.41.010196.001115|pmid=8546445|title=Ion Channels as Targets for Insecticides|journal=Annual Review of Entomology|volume=41|pages=163–90|year=1996|last1=Bloomquist|first1=Jeffrey R.}} </ref><ref>{{cite journal |doi=10.1002/arch.10112|pmid=14635176|title=Chloride channels as tools for developing selective insecticides|journal=Archives of Insect Biochemistry and Physiology|volume=54|issue=4|pages=145–56|year=2003|last1=Bloomquist|first1=Jeffrey R.}}</ref> 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.<ref>{{cite journal |doi=10.1016/0742-8413(93)90138-b|title=Toxicology, mode of action and target site-mediated resistance to insecticides acting on chloride channels|journal=Comparative Biochemistry and Physiology C|volume=106|issue=2|pages=301–314|year=1993|last1=Bloomquist|first1=Jeffrey R.|pmid=7904908}}</ref>{{dubious|reason=Turtles are also not protostomes, but they appear affected (see the ivermectin article ref). So are border collies with the MDR1 mutation. The role of the blood-brain barrier in selectivity should be mentioned.|date=November 2023}}<ref name="Wolstenholme-2012" /> Together with the milbemycins, avermectins belong to IRAC group 6.<ref>{{cite journal |last=Sparks |first=Thomas C |last2=Storer |first2=Nicholas |last3=Porter |first3=Alan |last4=Slater |first4=Russell |last5=Nauen |first5=Ralf |date=2021 |title=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 |journal=Pest Management Science |volume=77 |issue=6 |pages=2609–2619 |doi=10.1002/ps.6254 |issn=1526-498X |pmc=8248193 |pmid=33421293 |doi-access=free}}</ref>

== Toxicity and side effects == Resistance to avermectins has been reported, which suggests moderation in use.<ref name="Clark-et-al-1995" /> Resistance in ''Caenorhabditis elegans'' has been observed by the most obvious route – variation of the glutamate-gated chloride channel.<ref name="Ghosh-et-al-2012" /><ref name="Horoszok-et-al-2001" /> Research on ivermectin, piperazine, and dichlorvos in combinations also shows potential for toxicity.<ref>{{cite journal |pmid=11487234|year=2000|last1=Toth|first1=L. A.|title=Toxicity evaluation of prophylactic treatments for mites and pinworms in mice|journal=Contemporary Topics in Laboratory Animal Science|volume=39|issue=2|pages=18–21|last2=Oberbeck|first2=C|last3=Straign|first3=C. M.|last4=Frazier|first4=S|last5=Rehg|first5=J. E.}}</ref> Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, nitric oxide, prostaglandin E2, and increase of intracellular concentration of Ca<sup>2+</sup>.<ref>{{cite journal |pmid=15500074|year=2003|last1=Viktorov|first1=A. V.|title=Effect of ivermectin on function of liver macrophages|journal=Bulletin of Experimental Biology and Medicine|volume=136|issue=6|pages=569–71|last2=Yurkiv|first2=V. A.|doi=10.1023/b:bebm.0000020206.23474.e9|s2cid=851108}}</ref> 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.<ref>{{cite journal |doi=10.2174/138920112800399059|pmid=22039794|title=Acute Human Toxicity of Macrocyclic Lactones|journal=Current Pharmaceutical Biotechnology|volume=13|issue=6|pages=999–1003|year=2012|last1=Yang|first1=Chen-Chang}}</ref><ref>{{cite news |last1=Peter |first1=John |title=Ivermectin |url=https://www.firstmedinc.com}}</ref>

== Avermectin biosynthesis == thumb|Diagram showing the schematic synthesis of avermectins The gene cluster for biosynthesis of avermectin from ''S. avermitilis'' has been sequenced.<ref name="PMID10449723">{{cite journal |bibcode=1999PNAS...96.9509I|doi=10.1073/pnas.96.17.9509|pmid=10449723|title=Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis|journal=Proceedings of the National Academy of Sciences|volume=96|issue=17|pages=9509–9514|year=1999|last1=Ikeda|first1=H.|last2=Nonomiya|first2=T.|last3=Usami|first3=M.|last4=Ohta|first4=T.|last5=Omura|first5=S.|pmc=22239|doi-access=free}}</ref> 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.<ref name="YoonKim2004">{{cite journal |doi=10.1007/s00253-003-1491-4|pmid=14689246|title=Avermectin: Biochemical and molecular basis of its biosynthesis and regulation|journal=Applied Microbiology and Biotechnology|volume=63|issue=6|pages=626–34|year=2004|last1=Yoon|first1=Y. J.|last2=Kim|first2=E.-S.|last3=Hwang|first3=Y.-S.|last4=Choi|first4=C.-Y.|s2cid=2578270}}</ref>

thumb|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.<ref name="YoonKim2004" /> 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.<ref name="YoonKim2004" /> The initial aglycon is subsequently released from the thioesterase domain of AVES 4 by formation of an intramolecular cyclic ester.<ref name="YoonKim2004" />

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.<ref name="YoonKim2004" /> AveF has NAD(P)H-dependent ketoreductase activity which reduces the C5 keto group to a hydroxyl.<ref name="YoonKim2004" /> AveC influences the dehydratase activity in module two (affecting C22-C23), although the mechanism by which it does this is not clear.<ref name="PMID10449723" /><ref name="YoonKim2004" /> AveD has SAM-dependent C5 O-methyltransferase activity.<ref name="YoonKim2004" /> 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.<ref name="YoonKim2004" />

Nine open reading frames (orf1 and aveBI-BVIII) are downstream of aveA4, which are known involved with glycosylation and sugar synthesis.<ref name="YoonKim2004" /> AveBII-BVIII are responsible for synthesis of dTDP-L-oleandrose and AveBI is responsible for glycosylation of the avermectin aglycon with the dTDP-sugar.<ref name="YoonKim2004" /> The sequence of orf1 suggests that its product will have reductase activity, but this functionality does not appear to be necessary for avermectin synthesis.<ref name="YoonKim2004" />

== 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.<ref>{{cite journal |doi=10.2183/pjab.87.13|title=Ivermectin, 'wonder drug' from Japan: the human use perspective.|journal=Proceedings of the Japan Academy. Series B, Physical and Biological Sciences|volume=87|issue=2|pages=13–28|year=2011|last1=Crump|first1=Andy|last2=Ōmura|first2=Satoshi|pmid=21321478 |pmc=3043740 |bibcode=2011PJAB...87...13C |doi-access=free}}</ref>

== See also == * Milbemycins are a chemically closely related group of parasiticides. * Avermectin/ivermectin glycorandomization

== References == {{reflist|2|refs= <ref name="Wolstenholme-2012">{{cite journal | last=Wolstenholme | first=Adrian J. | title=Glutamate-gated Chloride Channels | journal=Journal of Biological Chemistry | publisher=American Society for Biochemistry & Molecular Biology (ASBMB) | volume=287 | issue=48 | date=2012-10-04 | issn=0021-9258 | doi=10.1074/jbc.r112.406280 | pages=40232–40238| pmid=23038250 | pmc=3504739 | doi-access=free }}</ref> <ref name="Clark-et-al-1995">{{cite journal | last1=Clark | first1=J K | last2=Scott | first2=J G | last3=Campos | first3=F | last4=Bloomquist | first4=J R | title=Resistance to Avermectins: Extent, Mechanisms, and Management Implications | journal=Annual Review of Entomology | publisher=Annual Reviews | volume=40 | issue=1 | year=1995 | issn=0066-4170 | doi=10.1146/annurev.en.40.010195.000245 | pages=1–30 | pmid=7810984}}</ref> <ref name="Ghosh-et-al-2012">{{cite journal | last1=Ghosh | first1=R. | last2=Andersen | first2=E. C. | last3=Shapiro | first3=J. A. | last4=Gerke | first4=J. P. | last5=Kruglyak | first5=L. | title=Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in ''C. elegans'' | journal=Science | publisher=American Association for the Advancement of Science (AAAS) | volume=335 | issue=6068 | date=2012-02-02 | issn=0036-8075 | doi=10.1126/science.1214318 | pages=574–578| pmid=22301316 | pmc=3273849 | bibcode=2012Sci...335..574G }}</ref> <ref name="Horoszok-et-al-2001">{{cite journal | last1=Horoszok | first1=Lucy | last2=Raymond | first2=Valérie | last3=Sattelle | first3=David B | last4=Wolstenholme | first4=Adrian J | title=GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from ''Caenorhabditis elegans'' | journal=British Journal of Pharmacology | publisher=Wiley | volume=132 | issue=6 | year=2001 | issn=0007-1188 | doi=10.1038/sj.bjp.0703937 | pages=1247–1254| pmid=11250875 | pmc=1572670 | doi-access=free }}</ref> <ref name="Nobel">{{cite web | title=The Nobel Prize in Physiology or Medicine 2015 | website=Nobel Prize | date=2020-12-03 | url=http://www.nobelprize.org/prizes/medicine/2015/summary/ | access-date=2020-12-03}}</ref> }}

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Category:Antiparasitic agents Category:Polyketides