Insights from aquaporin structures into drug-resistant sleeping sickness

Trypanosoma brucei is the causal agent of African trypanosomiasis in humans and animals, the latter resulting in significant negative economic impacts in afflicted areas of the world. Resistance has arisen to the trypanocidal drugs pentamidine and melarsoprol through mutations in the aquaglyceroporin TbAQP2 that prevent their uptake. Here, we use cryogenic electron microscopy to determine the structure of TbAQP2 from T. brucei , bound to either the substrate glycerol or to the sleeping sickness drugs, pentamidine or melarsoprol. The drugs bind within the AQP2 channel at a site completely overlapping that of glycerol. Mutations leading to a drug-resistant phenotype were found in the channel lining. Molecular dynamics (MD) simulations showed the channel can be traversed by pentamidine, with a low energy binding site at the centre of the channel, flanked by regions of high energy association at the extracellular and intracellular ends. Drug-resistant TbAQP2 mutants are still predicted to bind pentamidine, but the much weaker binding in the centre of the channel observed in the MD simulations would be insufficient to compensate for the high energy processes of ingress and egress, hence impairing transport at pharmacologically relevant concentrations. The structures of drug-bound TbAQP2 represent a novel paradigm for drug–transporter interactions and are a new mechanism for targeting drugs in pathogens and human cells.

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Journal
eLife
Published
2025-12-31
DOI
https://doi.org/10.7554/elife.107460.3
Primary Topic
Trypanosoma species research and implications
Type
article
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article

Insights from aquaporin structures into drug-resistant sleeping sickness

Tom L. Blundell, Sundeep Chaitanya Vedithi, Harry P. de Koning, Robin Adam Corey et al.
eLife
Trypanosoma species research and implications
article

Insights from aquaporin structures into drug-resistant sleeping sickness

Tom L. Blundell, Sundeep Chaitanya Vedithi, Harry P. de Koning, Robin Adam Corey, Teresa Sprenger, Pablo Castro‐Hartmann, Marcos Gragera, Mark S.P. Sansom, Roberto Melero, J.M. Carazo, Modestas Matusevicius, Dimitri Y. Chirgadze, Mark Carrington, Marzuq A. Ungogo, Anastasiia Gusach, Rangana Warshamanage, Simone Weyand, Keitaro Yamashita, Christopher G. Tate, James N. Blaza, Pavel Afanasyev, Phillip J Stansfeld, Garib N Murshudov
article en

Abstract

Trypanosoma brucei is the causal agent of African trypanosomiasis in humans and animals, the latter resulting in significant negative economic impacts in afflicted areas of the world. Resistance has arisen to the trypanocidal drugs pentamidine and melarsoprol through mutations in the aquaglyceroporin TbAQP2 that prevent their uptake. Here, we use cryogenic electron microscopy to determine the structure of TbAQP2 from T. brucei , bound to either the substrate glycerol or to the sleeping sickness drugs, pentamidine or melarsoprol. The drugs bind within the AQP2 channel at a site completely overlapping that of glycerol. Mutations leading to a drug-resistant phenotype were found in the channel lining. Molecular dynamics (MD) simulations showed the channel can be traversed by pentamidine, with a low energy binding site at the centre of the channel, flanked by regions of high energy association at the extracellular and intracellular ends. Drug-resistant TbAQP2 mutants are still predicted to bind pentamidine, but the much weaker binding in the centre of the channel observed in the MD simulations would be insufficient to compensate for the high energy processes of ingress and egress, hence impairing transport at pharmacologically relevant concentrations. The structures of drug-bound TbAQP2 represent a novel paradigm for drug–transporter interactions and are a new mechanism for targeting drugs in pathogens and human cells.

eLifeVol. 14
Ahmadu Bello University (NG), MRC Laboratory of Molecular Biology (GB), Neurosciences Institute (US), University of Cambridge (GB), University of Warwick (GB), University of Oxford (GB), Lung Institute (US), Institute for Medical Research (MY), Scope e-Knowledge Center (India) (IN), Bioinformatics Institute (RU), Biomedical Research Institute (US), Biocom (US), Institute of Infection and Immunity (CA), University of York (GB), Thermo Fisher Scientific (Israel) (IL), University of Glasgow (GB)
Openalex Percentile: Top 27%
Trypanosoma species research and implications
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