Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole

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:Achcar, Dr Fiona and MacLeod, Professor Annette and Morrison, Dr Liam and Giordani, Dr Federica and Barrett, Professor Michael and Vincent, Dr Isabel and Dickens, Dr Nicholas and Crouch, Dr Kathryn
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 > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168436Wellcome 096980/ZMichael BarrettWellcome Trust (WELLCOTR)096980/Z/11/ZIII - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology