ArticleInternational journal for parasitology. Drugs and drug resistance2013
Identification of mutations in TgMAPK1 of Toxoplasma gondii conferring resistance to 1NM-PP1.
Article in International journal for parasitology. Drugs and drug resistance, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 27 citations in OpenAlex.
- Treatment with BKI-1748 afterAntimicrobial agents and chemotherapy · 2025Article
- In vitro evaluation of new 4-thiazolidinones on invasion and growth of Toxoplasma gondii.International journal for parasitology. Drugs and drug resistance · 2021Article
- Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis.Journal of medicinal chemistry · 2020Article
- Proteins with calmodulin-like domains: structures and functional roles.Cellular and molecular life sciences : CMLS · 2019Review
- Gain- and Loss-of-Function Screens Coupled to Next-Generation Sequencing for Antibiotic Mode of Action and Resistance Studies inAntimicrobial agents and chemotherapy · 2019Article
- Who Needs a Contractile Actomyosin Ring? The Plethora of Alternative Ways to Divide a Protozoan Parasite.Frontiers in cellular and infection microbiology · 2019Review
- Toxoplasma Calcium-Dependent Protein Kinase 1 Inhibitors: Probing Activity and Resistance Using Cellular Thermal Shift Assays.Antimicrobial agents and chemotherapy · 2018Article
- Drug Resistance inFrontiers in microbiology · 2018Review
- In vitro efficacy of bumped kinase inhibitors against Besnoitia besnoiti tachyzoites.International journal for parasitology · 2017Article
- Inorganic nanoparticles killInternational journal of nanomedicine · 2017Article
- Drugs in development for toxoplasmosis: advances, challenges, and current status.Drug design, development and therapy · 2017Review
- An improved method for introducing site-directed point mutation into the Toxoplasma gondii genome using CRISPR/Cas9.Parasitology international · 2016Article
- Characterization of a Toxoplasma gondii calcium calmodulin-dependent protein kinase homolog.Parasites & vectors · 2016Article
- Inhibition of Calcium-Dependent Protein Kinase 1 (CDPK1) In Vitro by Pyrazolopyrimidine Derivatives Does Not Correlate with Sensitivity of Cryptosporidium parvum Growth in Cell Culture.Antimicrobial agents and chemotherapy · 2016Article
- In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum.Antimicrobial agents and chemotherapy · 2015Article
- Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans.Trends in pharmacological sciences · 2015Review
- A single mutation in the gatekeeper residue in TgMAPKL-1 restores the inhibitory effect of a bumped kinase inhibitor on the cell cycle.International journal for parasitology. Drugs and drug resistance · 2015Article
- Bumped kinase inhibitor 1294 treats established Toxoplasma gondii infection.Antimicrobial agents and chemotherapy · 2014Article
- Forward genetic screening identifies a small molecule that blocks Toxoplasma gondii growth by inhibiting both host- and parasite-encoded kinases.PLoS pathogens · 2014Article
- Whole genome profiling of spontaneous and chemically induced mutations in Toxoplasma gondii.BMC genomics · 2014Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Toxoplasma gondii is an important food and waterborne pathogen that causes severe disease in immunocompromised patients. Bumped kinase inhibitors (BKIs) have an antiparasitic effect on T. gondii tachyzoite growth by targeting T. gondii calmodulin-domain protein kinase 1 (TgCDPK1). To identify mutations that confer resistance to BKIs, chemical mutagenesis was performed, followed by selection in media containing either 250 or 1000 nM 1NM-PP1. Whole-genome sequence analysis of resistant clones revealed single nucleotide mutations in T. gondii mitogen-activated protein kinase 1 (TgMAPK1) at amino acids 162 (L162Q) and 171 (I171N). Plasmid constructs having the TgMAPK1 L162Q mutant sequence successfully replaced native TgMAPK1 genome locus in the presence of 1000 nM 1NM-PP1. The inhibitory effect of 1NM-PP1 on cell division observed in the parent clone was decreased in 1NM-PP1-resistant clones; however, effects on parasite invasion and calcium-induced egress were similar in both parent and resistant clones. A plasmid construct expressing the full length TgMAPK1 splicing isoform with L162Q mutation successfully complemented TgMAPK1 function in the pressure of 250 nM 1NM-PP1 in plaque assay. 1NM-PP1-resistant clones showed resistance to other BKIs (3MB-PP1 and 3BrB-PP1) with different levels. Here we identify TgMAPK1 as a novel target for 1NM-PP1 activity. This inhibitory effect is mediated through inhibition of tachyzoite cell division, and can be overcome through mutations at multiple residues in TgMAPK1.
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Registered trials
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