Abstract
The recently launched veterinary anthelmintic drench for sheep (Novartis Animal Health Inc., Switzerland) containing the nematocide monepantel represents a new class of anthelmintics: the amino-acetonitrile derivatives (AADs), much needed in view of widespread resistance to the classical drugs. Recently, it was shown that the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus, are potential targets for AAD action. Both proteins belong to the DEG-3 subfamily of acetylcholine receptors, which are thought to be nematode-specific, and different from those targeted by the imidazothiazoles (e.g. levamisole). Here we provide further evidence that Cel-ACR-23 and Hco-MPTL-1-like subunits are involved in the monepantel-sensitive phenotype. We performed comparative genomics of ligand-gated ion channel genes from several nematodes and subsequently assessed their sensitivity to anthelmintics. The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC50<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti, which lack an ACR-23/MPTL-1 homolog, are insensitive (EC50>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.
Highlights
Nematode parasites of sheep represent one of the major constraints in the wool, meat and milk industries world wide [1]
The amino-acetonitrile derivatives (AADs) have been reported as a new class of synthetic anthelmintics active against gastro-intestinal nematodes of sheep [8] and a first drug from this family, monepantel, was, at the time of writing licensed to market in Australasia, Europe and Latin America (ZOLVIX; Novartis Animal Health Inc., Switzerland; [9])
ACR-23 and MPTL-1 are members of the DEG-3 subfamily of acetylcholine receptor subunit genes and distinct from those targeted by imidazothiazoles [16,17]
Summary
Nematode parasites of sheep represent one of the major constraints in the wool, meat and milk industries world wide [1]. A further study on mutant H. contortus isolates identified the gene monepantel-1 (Hco-mptl-1) as a major target candidate for AADs action in this species [8,10]. Both Cel-acr-23 and Hco-mptl-1 are predicted to encode a nicotinic acetylcholine receptor (nAChR) subunit. These belong to the superfamily of ligand-gated ion channel (LGIC) subunits. ACR-23 and MPTL-1 are members of the DEG-3 subfamily of acetylcholine receptor subunit genes and distinct from those targeted by imidazothiazoles [16,17] Members of this subfamily have so far only been found in nematodes and no cross-resistance between the AADs and the imidazothiazoles have been documented [8].
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