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Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence
Journal article   Open access   Peer reviewed

Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence

S K Katiyar, V R Gordon, G L McLaughlin and T D Edlind
Antimicrobial agents and chemotherapy, v 38(9), pp 2086-2090
Sep 1994
DOI: https://doi.org/10.1128/AAC.38.9.2086
PMID: 7811023
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1128/AAC.38.9.2086View
Published, Version of Record (VoR) Open

Abstract

Benzimidazoles - toxicity Predictive Value of Tests Trichomonas vaginalis - metabolism Cercopithecus aethiops Molecular Sequence Data Tubulin - metabolism Cryptosporidium parvum - drug effects Entamoeba histolytica - metabolism Giardia lamblia - metabolism Tubulin - chemistry Tubulin - physiology Antiprotozoal Agents - toxicity Binding Sites Vero Cells Amino Acid Sequence Acanthamoeba - metabolism Kidney - drug effects Acanthamoeba - drug effects Leishmania major - drug effects Kidney - cytology Antiprotozoal Agents - pharmacology Entamoeba histolytica - drug effects Cryptosporidium parvum - metabolism Sequence Homology, Amino Acid Encephalitozoon - drug effects Animals Leishmania major - metabolism Trichomonas vaginalis - drug effects Benzimidazoles - pharmacology Encephalitozoon - metabolism Giardia lamblia - drug effects
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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Collaboration types
Domestic collaboration
Web of Science research areas
Microbiology
Pharmacology & Pharmacy
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