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Trypanosoma brucei aquaglyceroporin 2 is a high-affinity transporter for pentamidine and melaminophenyl arsenic drugs and the main genetic determinant of resistance to these drugs

Munday, Jane C. ; Eze, Anthonius A. ; Baker, Nicola ; Glover, Lucy ; Clucas, Caroline ; Aguinaga Andrés, David ; Natto, Manal J. ; Teka, Ibrahim A. ; McDonald, Jennifer ; Lee, Rebecca S. ; Graf, Fabrice E. ; Ludin, Philipp ; Burchmore, Richard J. S. ; Turner, C. Michael R. ; Tait, Andy ; MacLeod, Annette ; Mäser, Pascal ; Barrett, Michael P. ; Horn, David ; De Koning, Harry P.

In: Journal of Antimicrobial Chemotherapy, 2014, vol. 69, no. 3, p. 651-663

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    Titel
    • Trypanosoma brucei aquaglyceroporin 2 is a high-affinity transporter for pentamidine and melaminophenyl arsenic drugs and the main genetic determinant of resistance to these drugs
    Autor
    • Munday, Jane C.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Eze, Anthonius A.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Baker, Nicola. London School of Hygiene and Tropical Medicine, London, UK
    • Glover, Lucy. London School of Hygiene and Tropical Medicine, London, UK
    • Clucas, Caroline. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Aguinaga Andrés, David. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Natto, Manal J.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Teka, Ibrahim A.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • McDonald, Jennifer. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Lee, Rebecca S.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Graf, Fabrice E.. Swiss Tropical and Public Health Institute, Basel, Switzerland
    • Ludin, Philipp. Swiss Tropical and Public Health Institute, Basel, Switzerland
    • Burchmore, Richard J. S.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Turner, C. Michael R.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Tait, Andy. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • MacLeod, Annette. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Mäser, Pascal. Swiss Tropical and Public Health Institute, Basel, Switzerland
    • Barrett, Michael P.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    • Horn, David. London School of Hygiene and Tropical Medicine, London, UK
    • De Koning, Harry P.. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Journal of Antimicrobial Chemotherapy, 2014, vol. 69, no. 3, p. 651-663. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:295477
    Summary
    Objectives Trypanosoma brucei drug transporters include the TbAT1/P2 aminopurine transporter and the high-affinity pentamidine transporter (HAPT1), but the genetic identity of HAPT1 is unknown. We recently reported that loss of T. brucei aquaglyceroporin 2 (TbAQP2) caused melarsoprol/pentamidine cross-resistance (MPXR) in these parasites and the current study aims to delineate the mechanism by which this occurs. Methods The TbAQP2 loci of isogenic pairs of drug-susceptible and MPXR strains of T. brucei subspecies were sequenced. Drug susceptibility profiles of trypanosome strains were correlated with expression of mutated TbAQP2 alleles. Pentamidine transport was studied in T. brucei subspecies expressing TbAQP2 variants. Results All MPXR strains examined contained TbAQP2 deletions or rearrangements, regardless of whether the strains were originally adapted in vitro or in vivo to arsenicals or to pentamidine. The MPXR strains and AQP2 knockout strains had lost HAPT1 activity. Reintroduction of TbAQP2 in MPXR trypanosomes restored susceptibility to the drugs and reinstated HAPT1 activity, but did not change the activity of TbAT1/P2. Expression of TbAQP2 sensitized Leishmania mexicana promastigotes 40-fold to pentamidine and >1000-fold to melaminophenyl arsenicals and induced a high-affinity pentamidine transport activity indistinguishable from HAPT1 by Km and inhibitor profile. Grafting the TbAQP2 selectivity filter amino acid residues onto a chimeric allele of AQP2 and AQP3 partly restored susceptibility to pentamidine and an arsenical. Conclusions TbAQP2 mediates high-affinity uptake of pentamidine and melaminophenyl arsenicals in trypanosomes and TbAQP2 encodes the previously reported HAPT1 activity. This finding establishes TbAQP2 as an important drug transporter