title: Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates.
abstract: Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol-pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates.
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland ; University of Basel, CH-4000 Basel, Switzerland.
authors.forename: Fabrice E
authors.initials: FE
authors.lastname: Graf
authors.affiliation: Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Baker
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Munday
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.affiliation: Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Horn
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland ; University of Basel, CH-4000 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mäser
mesh_terms: D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism*; D051400:Aquaporin 3 / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance; D005786:Gene Expression Regulation / Q000502:physiology; D008549:Melarsoprol / Q000494:pharmacology*; D010419:Pentamidine / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology; D014347:Trypanosoma brucei gambiense / Q000187:drug effects* / Q000235:genetics*
chemical_list: D051399:Aquaporin 2; D014344:Trypanocidal Agents; D051400:Aquaporin 3; D010419:Pentamidine; D008549:Melarsoprol
keywords: Aquaporin; Drug resistance; Human African trypanosomiasis; Melarsoprol; Pentamidine; Reverse genetics; Sleeping sickness; Trypanosoma brucei gambiense