Mutations Associated with Anthelmintic Drug Resistance

Author(s): R.N. Beech, A. Silvestre.

Journal Name:Anti-Infective Agents in Medicinal Chemistry

Volume 9 , Issue 3 , 2010

Abstract:

A major concern for helminth parasite control in human and animal health is the development of anthelmintic resistance. The mutations that lead to such resistance do so in several ways including, loss of drug binding, modification of response once the drug has bound and loss of the drug target altogether. Benzimidazole resistance is best characterized by amino acid substitutions at three positions of the beta-tubulin protein: F167Y, E198A and F200Y, each of which causes loss of drug binding. Macrocyclic lactone resistance has been linked in the laboratory to mutations in different ligand-gated chloride-channel subunit genes, Hco-glc-5, Hco-lgc-37 and Con-avr-14 with substitutions A159V, K159R and L256F. These alter the channel response to drug binding, reducing its effects, which can also be seen in vivo. Levamisole resistance, including pyrantel and other related compounds, has been more difficult to characterize. More recently, loss of specific acetylcholine gated ion-channels that are targeted by the drug has been demonstrated with functional and molecular evidence. The loss of specific ion-channel targets of both the macrocyclic lactones and the new monepantel also seems to be a more general mechanism of anthelmintic resistance that requires further study. Praziquantel resistance is associated with SNPs in the β subunit forming voltage-gated Ca2+ channels. By placing our knowledge of the characteristics of these mutations in a framework of their biochemistry, functional characteristics, population genetics and effects in vivo gives us a more comprehensive understanding of how these mutations behave. This in turn should ultimately help us to minimize their impact.

Keywords: Anthelmintic resistance, mutation, benzimidazole, macrocyclic lactone, levamisole, monepantel, praziquantel, beta-tubulin, ligand-gated ion-channel

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Article Details

VOLUME: 9
ISSUE: 3
Year: 2010
Page: [105 - 112]
Pages: 8
DOI: 10.2174/1871521411009030105
Price: $58