In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 16, No. 11 ( 2020-11-3), p. e1008932-
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1008932
DOI:
10.1371/journal.ppat.1008932.g001
DOI:
10.1371/journal.ppat.1008932.g002
DOI:
10.1371/journal.ppat.1008932.g003
DOI:
10.1371/journal.ppat.1008932.g004
DOI:
10.1371/journal.ppat.1008932.g005
DOI:
10.1371/journal.ppat.1008932.s001
DOI:
10.1371/journal.ppat.1008932.s002
DOI:
10.1371/journal.ppat.1008932.s003
DOI:
10.1371/journal.ppat.1008932.s004
DOI:
10.1371/journal.ppat.1008932.s005
DOI:
10.1371/journal.ppat.1008932.s006
DOI:
10.1371/journal.ppat.1008932.s007
DOI:
10.1371/journal.ppat.1008932.s008
DOI:
10.1371/journal.ppat.1008932.s009
DOI:
10.1371/journal.ppat.1008932.s010
DOI:
10.1371/journal.ppat.1008932.s011
DOI:
10.1371/journal.ppat.1008932.r001
DOI:
10.1371/journal.ppat.1008932.r002
DOI:
10.1371/journal.ppat.1008932.r003
DOI:
10.1371/journal.ppat.1008932.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2205412-1
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