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Ben Jones - Disentangling the role of Ascaris β-tubulin isotypes in the emergence of anthelmintic resistance
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Descriptif
Ascariasis affects nearly one billion people, predominantly in the developing world. Ascariasis also affects pigs globally and reduces production yields via decreased growth and condemnation of livers. The predominant drugs used to treat ascariasis are the benzimidazoles (BZ). Despite using BZ anthelmintics for decades and BZ resistance occurring in other helminths, there has been little work on resistance in pig ascariasis. Benzimidazoles work by interacting with β-tubulin and the mutations causing resistance are known in some nematodes. Seven β-tubulin isotypes were identified using Ascaris genome data, and expression profiles were analysed at various developmental stages. Only three of the seven isotypes were highly expressed, making these the most likely to influence drug susceptibility. In silico docking simulations were used to model how BZs interact with β-tubulin proteins from Ascaris isotypes. Benzimidazoles were docked in the binding pocket containing resistance associated residues. The β-tubulin-BZ models then underwent molecular dynamics simulations which showed that interaction between BZs and residue 198 are key to drug binding and mutations in this residue lead to reduced binding energy. Mutations at residue 200 may also lead to resistance by interfering with binding at residue 198. In conclusion, the key interactions vital for BZ binding with β-tubulins have been identified and show how mutations can lead to resistance in Ascaris.
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