The avermectins are a series of
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
s and
pesticide
Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and lampri ...
s used to treat parasitic worms and insect
pests
PESTS was an anonymous American activist group formed in 1986 to critique racism, tokenism, and exclusion in the art world. PESTS produced newsletters, posters, and other print material highlighting examples of discrimination in gallery represent ...
. They are a group of 16-membered macrocyclic
lactone
Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring.
Lactones are formed by intramolecular esterification of the co ...
derivatives with potent
anthelmintic
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 a ...
and
insecticidal
Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...
properties.
These naturally occurring compounds are generated as fermentation products by ''
Streptomyces avermitilis
''Streptomyces avermitilis'' is a species of bacteria in the genus ''Streptomyces''. This bacterium was discovered by Satoshi Ōmura in Shizuoka Prefecture, Japan.
The first complete genome sequence of ''S. avermitilis'' was completed in 2003. ...
'', a soil
actinomycete
The Actinomycetales is an order of Actinomycetota. A member of the order is often called an actinomycete. Actinomycetales are generally gram-positive and anaerobic and have mycelia in a filamentous and branching growth pattern. Some actinomycete ...
. Eight different avermectins were isolated in four pairs of homologue compounds, with a major (a-component) and minor (b-component) component usually in ratios of 80:20 to 90:10.
[ Other anthelmintics derived from the avermectins include ]ivermectin
Ivermectin (, '' EYE-vər-MEK-tin'') 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, today it is used to treat inf ...
, selamectin
Selamectin (trade names Revolution and Stronghold manufactured by Zoetis, and Revolt manufactured by Aurora Pharmaceuticals, among others) is a topical parasiticide and anthelminthic used on dogs and cats. It treats and prevents infections of ...
, doramectin
Doramectin (Dectomax) is a veterinary drug approved by the Food and Drug Administration (FDA) for the treatment of parasites such as gastrointestinal roundworms, lungworms, eyeworms, grubs, sucking lice and mange mites in cattle.
It is used ...
, eprinomectin
Eprinomectin (MK-397) is an avermectin used as a veterinary Topical medication, topical endectocide. It is a mixture of two chemical compounds, eprinomectin B1a and B1b.
References
Antiparasitic agents
Macrocycles
{{antiinfectiv ...
, and abamectin
Abamectin 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 (also called Avermectin B1), differ ...
.
Half of the 2015 Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
was awarded to William C. Campbell and 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 fo ...
for discovering avermectin, "the derivatives of which have radically lowered the incidence of river blindness
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 blindne ...
and lymphatic filariasis
Lymphatic filariasis is a human disease caused by parasitic worms known as filarial worms. Usually acquired in childhood, it is a leading cause of permanent disability worldwide. While most cases have no symptoms, some people develop a syndrome ...
, 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
Merck & Co., Inc. is an American multinational pharmaceutical company headquartered in Rahway, New Jersey, and is named for Merck Group, founded in Germany in 1668, of whom it was once the American arm. The company does business as Merck Sharp ...
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
''Heligmosomoides polygyrus'', previously named ''Nematospiroides dubius'', is a naturally occurring intestinal roundworm of rodents. It belongs to the family Trychostrongylidae, and male and female worms are morphologically distinguishable. The ...
'' 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).
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''.
Dosing
A commonly used therapy in recent times has been based on oral, parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
, topical, or spot topical (as in veterinary flea repellant "drops") administration of avermectins. They show activity against a broad range of nematode
The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...
s and arthropod
Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
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). Unlike the macrolide
The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...
or polyene
In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, result ...
antibiotics, they lack significant antibacterial or antifungal activities.
Mechanism of action
The avermectins block the transmission of electrical activity in invertebrate nerve and muscle cells mostly by enhancing the effects of glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
at the glutamate-gated chloride channel
Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Severa ...
that is specific to protostome
Protostomia () is the clade of animals once thought to be characterized by the formation of the organism's mouth before its anus during embryogenesis, embryonic development. This nature has since been discovered to be extremely variable among Pro ...
invertebrates,
with minor effects on gamma-aminobutyric acid receptors.
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.
Toxicity and side effects
Resistance to avermectins has been reported, which suggests moderation in use. Resistance in ''Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'' has been observed by the most obvious route – variation of the glutamate-gated chloride channel
Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Severa ...
. Research on ivermectin
Ivermectin (, '' EYE-vər-MEK-tin'') 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, today it is used to treat inf ...
, piperazine
Piperazine () is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste.
The piperazines are a broad ...
, and dichlorvos
Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, commonly abbreviated as an DDVP) is an organophosphate widely used as an insecticide to control household pests, in public health, and protecting stored products from insects. The compound has b ...
in combinations also shows potential for toxicity. Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
, prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
E2, and increase of intracellular concentration of Ca2+. Adverse effects are usually transient; severe effects are rare and probably occur only with substantial overdose, but include coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
, hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
, and respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
, which can lead to death. No specific therapy exists, but symptomatic management usually leads to a favorable prognosis.
Avermectin biosynthesis
The gene cluster for biosynthesis of avermectin from ''S. avermitilis'' has been sequenced. The avermectin biosynthesis gene cluster encodes enzymes responsible for four steps of avermectin production: 1) production of the avermectin aglycon An aglycone (aglycon or genin) is the compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid molecule.
Detection
A way to identify aglycone ...
by polyketide synthases
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
, 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.
The avermectin initial aglycon is synthesized by the polyketide synthase
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
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. 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. 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. AveF has NAD(P)H-dependent ketoreductase activity which reduces the C5 keto group to a hydroxyl. AveC influences the dehydratase activity in module two (affecting C22-C23), although the mechanism by which it does this is not clear. AveD has SAM-dependent C5 O-methyltransferase activity. Whether AveC or AveD acts on the aglycon determines whether the resulting avermectin aglycon will produce avermectin, respectively.
Nine open reading frames (orf1 and aveBI-BVIII) are downstream of aveA4, which are known involved with glycosylation and sugar synthesis. AveBII-BVIII are responsible for synthesis of dTDP-L-oleandrose and AveBI is responsible for glycosylation of the avermectin aglycon with the dTDP-sugar. The sequence of orf1 suggests that its product will have reductase activity, but this functionality does not appear to be necessary for avermectin synthesis.
Other uses
Abamectin
Abamectin 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 (also called Avermectin B1), differ ...
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.
See also
* Milbemycin 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. s are a chemically closely related group of parasiticides.
* Avermectin/ivermectin glycorandomization
Glycorandomization, is a drug discovery and drug development technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile me ...
References
{{Endectocides
Antiparasitic agents
Polyketides