Biochemistry of benzimidazole resistance.

Heavy reliance on the benzimidazole (BZ) anthelmintics since their introduction in the 1960's for the control of gastrointestinal parasites of livestock has led to widespread BZ resistance in target parasite species. The BZs exert their primary action by binding to tubulin, the major protein component of microtubules. This review discusses the biochemistry of the interaction between the BZs and tubulin from mammalian and BZ-resistant and -susceptible parasite sources, exploring aspects of the selective toxicity of these drugs and examining the mechanism of BZ resistance. Although tubulin is a highly conserved protein present in both the host and the parasite, the BZs demonstrate relatively low mammalian toxicity. The selectivity of these drugs can be explained by the much higher affinity of the BZs for tubulin from the parasite at 37 degrees C compared to their affinity for tubulin from the host. This difference in affinity reflects the considerably slower rate of BZ dissociation from parasite tubulin. BZ-resistance in parasitic nematodes is characterised by a loss of high affinity BZ-parasite tubulin interactions and a corresponding increase in lower affinity interactions, although there are still significant differences between BZ-resistant parasite tubulin and tubulin from the host. These differences suggest the potential for the design of new generation BZs active against 'BZ-resistant' parasites.