Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates

Int J Parasitol Drugs Drug Resist. 2015 May 7;5(2):65-8. doi: 10.1016/j.ijpddr.2015.04.002. eCollection 2015 Aug.

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.

Keywords: Aquaporin; Drug resistance; Human African trypanosomiasis; Melarsoprol; Pentamidine; Reverse genetics; Sleeping sickness; Trypanosoma brucei gambiense.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aquaporin 2 / genetics
  • Aquaporin 2 / metabolism*
  • Aquaporin 3 / genetics
  • Aquaporin 3 / metabolism*
  • Drug Resistance
  • Gene Expression Regulation / physiology
  • Melarsoprol / pharmacology*
  • Pentamidine / pharmacology*
  • Trypanocidal Agents / pharmacology
  • Trypanosoma brucei gambiense / drug effects*
  • Trypanosoma brucei gambiense / genetics*

Substances

  • Aquaporin 2
  • Trypanocidal Agents
  • Aquaporin 3
  • Pentamidine
  • Melarsoprol