Author: Federica Giordani, Daniel Paape, Isabel M. Vincent, Andrew W. Pountain, Fernando Fernández-Cortés, Eva Rico, Ning Zhang, Liam J. Morrison, Yvonne Freund, Michael J. Witty, Rosemary Peter, Darren Y. Edwards, Jonathan M. Wilkes, Justin J. J. van der Hooft, Clément Regnault, Kevin D. Read, David Horn, Mark C. Field, Michael P. Barrett
Year: 2020
About this Publication:
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 opies 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.
Grant: PLSHL2
Subject Areas: Research and Development
Diseases: Trypanosomosis
URL https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008932
Keywords:
T. brucei, T. vivax, Trypanocidal benzoxaboroles, Trypanosoma congolense
