Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei

Clare F. Collett, Carl Kitson, Nicola Baker, Heather B. Steele-Stallard, Marie-Victoire Santrot, Sebastian Hutchinson, David Horn, Sam Alsford (Lead / Corresponding author)

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Abstract

The arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by toxicity and emergent resistance. Furthermore, our understanding of drug mode of action and potential routes to resistance is limited. Forward genetic approaches have revolutionized our understanding of drug mode of action in the related kinetoplastid parasite Trypanosoma brucei. Therefore, we screened our genome-scale T. brucei RNA interference (RNAi) library against the current antileishmanial drugs sodium stibogluconate (antimonial), paromomycin, miltefosine, and amphotericin B. Identification of T. brucei orthologues of the known Leishmania antimonial and miltefosine plasma membrane transporters effectively validated our approach, while a cohort of 42 novel drug efficacy determinants provides new insights and serves as a resource. Follow-up analyses revealed the antimonial selectivity of the aquaglyceroporin TbAQP3. A lysosomal major facilitator superfamily transporter contributes to paromomycin-aminoglycoside efficacy. The vesicle-associated membrane protein TbVAMP7B and a flippase contribute to amphotericin B and miltefosine action and are potential cross-resistance determinants. Finally, multiple phospholipid-transporting flippases, including the T. brucei orthologue of the Leishmania miltefosine transporter, a putative -subunit/CDC50 cofactor, and additional membrane-associated hits, affect amphotericin B efficacy, providing new insights into mechanisms of drug uptake and action. The findings from this orthology-based chemogenomic profiling approach substantially advance our understanding of antileishmanial drug action and potential resistance mechanisms and should facilitate the development of improved therapies as well as surveillance for drug-resistant parasites.

Original languageEnglish
Article numbere00795-19
Pages (from-to)1-19
Number of pages19
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number8
Early online date3 Jun 2019
DOIs
Publication statusPublished - Aug 2019

Keywords

  • Leishmania
  • Trypanosoma
  • amphotericin B
  • aquaglyceroporin
  • major facilitator superfamily transporter
  • miltefosine
  • paromomycin
  • phospholipid-transporting ATPase
  • sodium stibogluconate
  • vesicle-associated membrane protein

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    Collett, C. F., Kitson, C., Baker, N., Steele-Stallard, H. B., Santrot, M-V., Hutchinson, S., Horn, D., & Alsford, S. (2019). Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei. Antimicrobial Agents and Chemotherapy, 63(8), 1-19. [e00795-19]. https://doi.org/10.1128/AAC.00795-19