A new class of anthelmintics effective against drug-resistant nematodes

• Published in: Nature 2008-03, Vol.452 (7184), p.176-180
• Main Authors: Kaminsky, Ronald, Ducray, Pierre, Jung, Martin, Clover, Ralph, Rufener, Lucien, Bouvier, Jacques, Weber, Sandra Schorderet, Wenger, Andre, Wieland-Berghausen, Susanne, Goebel, Thomas, Gauvry, Noelle, Pautrat, François, Skripsky, Thomas, Froelich, Olivier, Komoin-Oka, Clarisse, Westlund, Bethany, Sluder, Ann, Mäser, Pascal
• Format: Article
• Language: English
• Subjects: Aging; Amino Acid Sequence; Aminoacetonitrile - adverse effects; Aminoacetonitrile - analogs & derivatives; Aminoacetonitrile - pharmacokinetics; Aminoacetonitrile - pharmacology; Animals; Anthelmintics - chemistry; Anthelmintics - classification; Anthelmintics - pharmacokinetics; Anthelmintics - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cattle; Cattle Diseases - drug therapy; Cattle Diseases - parasitology; Drug resistance; Drug Resistance - genetics; Drug therapy; Humanities and Social Sciences; Larva - drug effects; Larva - genetics; Livestock; Mammals; Medical sciences; Mode of action; Molecular Sequence Data; multidisciplinary; Nematoda; Nematoda - drug effects; Nematoda - genetics; Nematoda - physiology; Nematodes; Parasitic Diseases, Animal - drug therapy; Parasitic Diseases, Animal - parasitology; Pathology; Pharmacology. Drug treatments; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Science; Science (multidisciplinary); Sheep - parasitology; Sheep Diseases - drug therapy; Sheep Diseases - parasitology; Worms
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature06722

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics—the benzimidazoles, imidazothiazoles and macrocyclic lactones—has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics. A new class of anthelmintic The use of drugs to control pathogenic roundworms in farm animals, an important tool of modern livestock management, is being undermined by the spread of multidrug resistance against all three types of anthelmintic currently available. No new anthelmintic class has reached the market in the past 25 years save the cyclodepsipeptides, indicated for use in cats but not in livestock. Kaminsky et al . now report the discovery of a new class of anthelmintics — amino-acetonitrile derivatives — that appear to act via acetylcholine receptors specific to nematodes. They are effective against various livestock pathogens, and if successful in animals, may also provide alternative drugs for use in humans, where drug resistance is also increasing. The discovery of a new chemical class of anthelmintics that seem to act through a novel mechanism is reported. These small molecules are efficacious against various livestock pathogenic-nematode species.