Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

Ali H. Alghamdi, Jane C. Munday, Gustavo Daniel Campagnaro, Dominik Gurvic, Fredrik Svensson, Chinyere E. Okpara, Arvind Kumar, Juan F. Quintana, Maria Esther Martin Abril, Patrik Milić, Laura Watson, Daniel Paape, Luca Settimo, Anna Dimitriou, Joanna Wielinska, Graeme Smart, Laura F. Anderson, Christopher M. Woodley, Siu Pui Ying Kelley, Hasan M. S. IbrahimFabian Hulpia, Mohammed I. Al-Salabi, Anthonius A. Eze, Simon Gudin, Mark Field, Christophe Dardonville, Richard R . Tidwell, Mark Carrington, Paul M. O'Neill, David W . Boykin, Ulrich Zachariae, Harry P. de Koning

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Abstract

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 crossresistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.
Original languageEnglish
Article numbere56416
Number of pages33
JournaleLife
Volume9
Early online date7 Aug 2020
DOIs
Publication statusPublished - 4 Sep 2020

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    Alghamdi, A. H., Munday, J. C., Campagnaro, G. D., Gurvic, D., Svensson, F., Okpara, C. E., Kumar, A., Quintana, J. F., Abril, M. E. M., Milić, P., Watson, L., Paape, D., Settimo, L., Dimitriou, A., Wielinska, J., Smart, G., Anderson, L. F., Woodley, C. M., Kelley, S. P. Y., ... de Koning, H. P. (2020). Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei. eLife, 9, [e56416]. https://doi.org/10.7554/eLife.56416