ArticleThe Journal of biological chemistry2014
In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug-binding site and altered growth.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 69 citations in OpenAlex.
- Twenty Years of Benzimidazole Scaffold Optimization in Antiparasitic Drug Discovery.ChemMedChem · 2026Review
- Virtual screening and molecular dynamics analysis of Plasmodium falciparum dihydroorotate dehydrogenase (DHODH) inhibitors targeting pyrimidine biosynthesis pathway.Folia microbiologica · 2026Article
- Potent acridone antimalarial against all three life stages of Plasmodium.Nature communications · 2026Article
- Article
- Replication stress increases de novo CNVs across the malaria parasite genome.Nucleic acids research · 2026Article
- Replication stress increases de novo CNVs across the malaria parasite genome.bioRxiv : the preprint server for biology · 2025Article
- Direct long-read visualization reveals hidden variation in GCH1 gene copy number and precise expansion steps.BMC genomics · 2025Article
- Direct long read visualization reveals metabolic interplay between two antimalarial drug targets.bioRxiv : the preprint server for biology · 2023Article
- Article
- Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues.International journal for parasitology. Drugs and drug resistance · 2022Article
- Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.Journal of medicinal chemistry · 2021Article
- The contribution of extrachromosomal DNA to genome plasticity in malaria parasites.Molecular microbiology · 2021Article
- Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2021Article
- Resistance to Some But Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in aACS infectious diseases · 2020Article
- The resistome and genomic reconnaissance in the age of malaria elimination.Disease models & mechanisms · 2019Review
- In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model.Science translational medicine · 2019Article
- Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265.ACS infectious diseases · 2019Article
- Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.Science (New York, N.Y.) · 2018Article
- Selection ofProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Identification of Collateral Sensitivity to Dihydroorotate Dehydrogenase Inhibitors in Plasmodium falciparum.ACS infectious diseases · 2018Article
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild-type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity.
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Registered trials
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