Disentangling the role of Ascaris β-tubulin isotypes in the emergence of anthelmintic resistance.

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Authors

B P Jones2; A H van Vliet2; E J Lacourse1; M Betson2
1 Liverpool School of Tropical Medicine / UoL, UK;  2 University of Surrey, UK

Discussion

Ascaris lumbricoides and Ascaris suum are intestinal roundworms that infect humans and pigs respectively and cause the disease known as ascariasis. Ascariasis affects nearly one billion people, with chronic infections leading to reduced growth and cognitive ability. Ascariasis affects pigs worldwide and can reduce production yields via decreased growth and condemnation of livers. The predominant drugs used to treat ascariasis are the benzimidazoles (BZ). Despite the farming industry using these drugs for decades, and BZ resistance occurring in numerous livestock helminths, there has been little work into the development of resistance in pig ascariasis. Benzimidazoles work by interacting with β-tubulin and the mutations causing resistance are known in some nematodes. In most nematodes there are multiple β-tubulin isotypes. Only a few of these are expressed at high levels, with others being restricted to specialised cells or specific developmental stages. Seven β-tubulin isotypes were identified by analysis of Ascaris genome sequences, and the expression profiles of these 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 wildtype and mutated β-tubulin proteins from Ascaris suum isotypes. The BZ albendazole sulfoxide was docked within the binding pocket containing the residues associated with resistance. The β-tubulin-BZ models then underwent molecular dynamics simulations. The results showed that interaction between BZs and residue 198 is 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.  These results highlight the key interactions between BZ and specific residues as well as the direct impact that some mutations have on drug binding.

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