and Ascaris suum
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.
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