A conserved coccidian gene is involved in Toxoplasma sensitivity to the anti-apicomplexan compound, tartrolon E.
Anti-apicomplexan
CRISPR/Cas9
Drug discovery
Natural products
Tartrolon E
Toxoplasma
Journal
International journal for parasitology. Drugs and drug resistance
ISSN: 2211-3207
Titre abrégé: Int J Parasitol Drugs Drug Resist
Pays: Netherlands
ID NLM: 101576715
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
16
06
2020
revised:
20
07
2020
accepted:
23
07
2020
pubmed:
2
8
2020
medline:
21
8
2021
entrez:
2
8
2020
Statut:
ppublish
Résumé
New treatments for the diseases caused by apicomplexans are needed. Recently, we determined that tartrolon E (trtE), a secondary metabolite derived from a shipworm symbiotic bacterium, has broad-spectrum anti-apicomplexan parasite activity. TrtE inhibits apicomplexans at nM concentrations in vitro, including Cryptosporidium parvum, Toxoplasma gondii, Sarcocystis neurona, Plasmodium falciparum, Babesia spp. and Theileria equi. To investigate the mechanism of action of trtE against apicomplexan parasites, we examined changes in the transcriptome of trtE-treated T. gondii parasites. RNA-Seq data revealed that the gene, TGGT1_272370, which is broadly conserved in the coccidia, is significantly upregulated within 4 h of treatment. Using bioinformatics and proteome data available on ToxoDB, we determined that the protein product of this tartrolon E responsive gene (trg) has multiple transmembrane domains, a phosphorylation site, and localizes to the plasma membrane. Deletion of trg in a luciferase-expressing T. gondii strain by CRISPR/Cas9 resulted in a 68% increase in parasite resistance to trtE treatment, supporting a role for the trg protein product in the response of T. gondii to trtE treatment. Trg is conserved in the coccidia, but not in more distantly related apicomplexans, indicating that this response to trtE may be unique to the coccidians, and other mechanisms may be operating in other trtE-sensitive apicomplexans. Uncovering the mechanisms by which trtE inhibits apicomplexans may identify shared pathways critical to apicomplexan parasite survival and advance the search for new treatments.
Identifiants
pubmed: 32738587
pii: S2211-3207(20)30020-8
doi: 10.1016/j.ijpddr.2020.07.003
pmc: PMC7394737
pii:
doi:
Substances chimiques
Antiparasitic Agents
0
Lactones
0
tartrolon E
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-7Subventions
Organisme : NCCIH NIH HHS
ID : R21 AT009174
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
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