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Research Article

Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence.

S K Katiyar, V R Gordon, G L McLaughlin, T D Edlind
S K Katiyar
Medical College of Pennsylvania, Philadelphia 19129.
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V R Gordon
Medical College of Pennsylvania, Philadelphia 19129.
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G L McLaughlin
Medical College of Pennsylvania, Philadelphia 19129.
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T D Edlind
Medical College of Pennsylvania, Philadelphia 19129.
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DOI: 10.1128/AAC.38.9.2086
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ABSTRACT

Benzimidazoles have been widely used since the 1960s as anthelmintic agents in veterinary and human medicine and as antifungal agents in agriculture. More recently, selected benzimidazole derivatives were shown to be active in vitro against two protozoan parasites, Trichomonas vaginalis and Giardia lamblia, and clinical studies with AIDS patients have suggested that microsporidia are susceptible as well. Here, we first present in vitro susceptibility data for T. vaginalis and G. lamblia using an expanded set of benzimidazole derivatives. Both parasites were highly susceptible to four derivatives, including mebendazole, flubendazole, and fenbendazole (50% inhibitory concentrations of 0.005 to 0.16 microgram/ml). These derivatives also had lethal activity that was time dependent: 90% of T. vaginalis cells failed to recover following a 20-h exposure to mebendazole at 0.17 microgram/ml. G. lamblia, but not T. vaginalis, was highly susceptible to five additional derivatives. Next, we examined in vitro activity of benzimidazoles against additional protozoan parasites: little or no activity was observed against Entamoeba histolytica, Leishmania major, and Acanthamoeba polyphaga. Since the microtubule protein beta-tubulin has been identified as the benzimidazole target in helminths and fungi, potential correlations between benzimidazole activity and beta-tubulin sequence were examined. This analysis included partial sequences (residues 108 to 259) from the organisms mentioned above, as well as the microsporidia Encephalitozoon hellem and Encephalitozoon cuniculi and the sporozoan Cryptosporidium parvum. beta-tubulin residues Glu-198 and, in particular, Phe-200 are strong predictors of benzimidazole susceptibility; both are present in Encephalitozoon spp. but absent in C. parvum.

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Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence.
S K Katiyar, V R Gordon, G L McLaughlin, T D Edlind
Antimicrobial Agents and Chemotherapy Sep 1994, 38 (9) 2086-2090; DOI: 10.1128/AAC.38.9.2086

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Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence.
S K Katiyar, V R Gordon, G L McLaughlin, T D Edlind
Antimicrobial Agents and Chemotherapy Sep 1994, 38 (9) 2086-2090; DOI: 10.1128/AAC.38.9.2086
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