1 research outputs found
Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance
to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected
for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s
unique architecture permits pentamidine permeation through its central pore and show how
specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2
amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics
demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2,
driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic
species. We also identify the structural determinants that make pentamidine a permeant although
most other diamidine drugs are excluded. Our results have wide-ranging implications for
optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in
aquaporin permeation may allow the pharmacological exploitation of other members of this
ubiquitous gene family