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

Alghamdi, A. et al. (2020) Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei. eLife, 9, e56416. (doi: 10.7554/eLife.56416) (PMID:32762841) (PMCID:PMC7473772)

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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 cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paape, Dr Daniel and Quintana, Dr Juan and Munday, Dr Jane and Alghamdi, Ali and Campagnaro, Gustavo and De Koning, Professor Harry and Al-Salabi, Dr Mohammed and O'Neill, Dr Paul and Settimo, Dr Luca
Creator Roles:
De Koning, H.Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Supervision, Writing – original draft, Writing – review and editing
Alghamdi, A.Investigation
Munday, J.Investigation, Methodology
Campagnaro, G.Investigation
Quintana, J.Investigation
Paape, D.Investigation
Settimo, L.Investigation, Methodology, Validation
Al-Salabi, M.Investigation
O'Neill, P.Resources, Supervision
Authors: Alghamdi, A., Munday, J. C., Campagnaro, G. D., Gurvic, D., Svensson, F., Okpara, C. E., Kumar, A., Quintana, J., Martin Abril, M. E., Milić, P., Watson, L., Paape, D., Settimo, L., Dimitriou, A., Wielinska, J., Smart, G., Anderson, L. F., Woodley, C. M., Kelly, S. P. Y., Ibrahim, H. M., Hulpia, F., Al-Salabi, M. I., Eze, A. A., Teka, I. A., Gudin, S., Field, M., Dardonville, C., Tidwell, R. R., Carrington, M., O'Neill, P., Boykin, D. W., Zachariae, U., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
Published Online:07 August 2020
Copyright Holders:Copyright © 2020 Alghamdi et al.
First Published:First published in eLife 9: e56416
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
160073Drug resistance in African trypanosomesHarry De KoningMedical Research Council (MRC)G0701258III - Parasitology