Steketee, P. C., Giordani, F. , Vincent, I. M. , Crouch, K. , Achcar, F. , Dickens, N. J. , Morrison, L. J., MacLeod, A. and Barrett, M. P. (2021) Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole. PLoS Neglected Tropical Diseases, 15(11), e0009939. (doi: 10.1371/journal.pntd.0009939) (PMID:34752454) (PMCID:PMC8648117)
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Abstract
Subspecies of the protozoan parasite Trypanosoma brucei are the causative agents of Human African Trypanosomiasis (HAT), a debilitating neglected tropical disease prevalent across sub-Saharan Africa. HAT case numbers have steadily decreased since the start of the century, and sustainable elimination of one form of the disease is in sight. However, key to this is the development of novel drugs to combat the disease. Acoziborole is a recently developed benzoxaborole, currently in advanced clinical trials, for treatment of stage 1 and stage 2 HAT. Importantly, acoziborole is orally bioavailable, and curative with one dose. Recent studies have made significant progress in determining the molecular mode of action of acoziborole. However, less is known about the potential mechanisms leading to acoziborole resistance in trypanosomes. In this study, an in vitro-derived acoziborole-resistant cell line was generated and characterised. The AcoR line exhibited significant cross-resistance with the methyltransferase inhibitor sinefungin as well as hypersensitisation to known trypanocides. Interestingly, transcriptomics analysis of AcoR cells indicated the parasites had obtained a procyclic- or stumpy-like transcriptome profile, with upregulation of procyclin surface proteins as well as differential regulation of key metabolic genes known to be expressed in a life cycle-specific manner, even in the absence of major morphological changes. However, no changes were observed in transcripts encoding CPSF3, the recently identified protein target of acoziborole. The results suggest that generation of resistance to this novel compound in vitro can be accompanied by transcriptomic switches resembling a procyclic- or stumpy-type phenotype.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Vincent, Dr Isabel and Dickens, Dr Nicholas and Crouch, Dr Kathryn and Achcar, Dr Fiona and MacLeod, Professor Annette and Morrison, Dr Liam and Giordani, Dr Federica and Barrett, Professor Michael |
| Creator Roles: | Giordani, F.Data curation, Investigation, Methodology Vincent, I. M.Conceptualization, Investigation, Validation Crouch, K.Conceptualization, Methodology Achcar, F.Conceptualization, Investigation, Methodology, Validation Dickens, N. J.Conceptualization, Formal analysis, Methodology, Supervision Morrison, L. J.Writing – review and editing MacLeod, A.Conceptualization, Funding acquisition, Investigation, Methodology, Supervision Barrett, M. P.Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review and editing |
| Authors: | Steketee, P. C., Giordani, F., Vincent, I. M., Crouch, K., Achcar, F., Dickens, N. J., Morrison, L. J., MacLeod, A., and Barrett, M. P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | PLoS Neglected Tropical Diseases |
| Publisher: | Public Library of Science |
| ISSN: | 1935-2727 |
| ISSN (Online): | 1935-2735 |
| Published Online: | 09 November 2021 |
| Copyright Holders: | Copyright © 2021 Steketee et al. |
| First Published: | First published in PLoS Neglected Tropical Diseases 15(11): e0009939 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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