Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs

Giordani, F. et al. (2020) Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs. PLoS Pathogens, 16(11), e1008932. (doi: 10.1371/journal.ppat.1008932) (PMID:33141865) (PMCID:PMC7710103)

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Abstract

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.

Item Type:Articles
Additional Information:Funding: This work was funded by a BBSRC grant (BB/S001034/1) to L.J.M. and M.P.B., a Wellcome Trust Senior Investigator Award to D.H. (100320/Z/12/Z), a Wellcome Trust Centre Award (203134/Z/16/Z) to Dundee and a core grant to the Wellcome Centre for Integrative Parasitology (104111/Z/14/Z).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paape, Dr Daniel and Fernandez-Cortes, Dr Fernando and Regnault, Mr Clement and Vincent, Dr Isabel and Wilkes, Dr Jonathan and Van Der Hooft, Mr Justin and Pountain, Andrew and Morrison, Dr Liam and Zhang, Ning and Giordani, Dr Federica and Barrett, Professor Michael
Creator Roles:
Giordani, F.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing
Paape, D.Formal analysis, Investigation, Project administration, Validation, Writing – original draft
Vincent, I.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing
Pountain, A.Conceptualization, Data curation, Formal analysis, Investigation, Software, Visualization, Writing – review and editing
Fernandez-Cortes, F.Conceptualization, Data curation, Formal analysis, Investigation, Writing – review and editing
Zhang, N.Conceptualization, Investigation, Methodology
Morrison, L. J.Conceptualization, Funding acquisition, Validation, Writing – review and editing
Wilkes, J.Formal analysis, Methodology, Software
Van Der Hooft, J.Data curation, Methodology, Writing – review and editing
Regnault, C.Data curation, Investigation, Methodology
Barrett, M. P.Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – review and editing
Authors: Giordani, F., Paape, D., Vincent, I., Pountain, A., Fernandez-Cortes, F., Rico, E., Zhang, N., Morrison, L. J., Freund, Y., Witty, M. J., Peter, R., Edwards, D. Y., Wilkes, J., Van Der Hooft, J., Regnault, C., Read, K. D., Horn, D., Field, M. C., and Barrett, M. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7374
Published Online:03 November 2020
Copyright Holders:Copyright © 2020 Giordani et al.
First Published:First published in PLoS Pathogens 16(11):e1008932
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302761Tracking isometamidium resistance in livestock trypanaosomesMichael BarrettBiotechnology and Biological Sciences Research Council (BBSRC)BB/S001034/1III - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology