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 |
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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: | Pountain, Andrew and Morrison, Dr Liam and Paape, Dr Daniel and Giordani, Dr Federica and Fernandez-Cortes, Dr Fernando and Barrett, Professor Michael and Regnault, Mr Clement and Vincent, Dr Isabel and Wilkes, Dr Jonathan and Van Der Hooft, Mr Justin |
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 > School of Infection & Immunity |
Journal Name: | PLoS Pathogens |
Publisher: | Public Library of Science |
ISSN: | 1553-7366 |
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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