ArticleACS infectious diseases2019
Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265.
Article in ACS infectious diseases, 2019. 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, 57 citations in OpenAlex.
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- Identification of an Orally Efficacious Imidazo[4,5-Journal of medicinal chemistry · 2026Article
- Advancements in CRISPR-Cas Systems for Genome Editing towards Eradication of Human Microbial Pathogens.Molecular biotechnology · 2026Review
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- Validated antimalarial drug target discovery using genome-scale metabolic modeling.Antimicrobial agents and chemotherapy · 2025Article
- Direct long-read visualization reveals hidden variation in GCH1 gene copy number and precise expansion steps.BMC genomics · 2025Article
- The PfK13 G533S mutation confers artemisinin partial resistance in multiple genetic backgrounds ofAntimicrobial agents and chemotherapy · 2025Article
- Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.Journal of medicinal chemistry · 2025Article
- Identification of genetic variations linked to buparvaquone resistance in Theileria annulata infecting dairy cattle in India.PloS one · 2025Article
- Integral Solvent-Induced Protein Precipitation for Target-Engagement Studies inACS infectious diseases · 2024Article
- Direct long read visualization reveals metabolic interplay between two antimalarial drug targets.bioRxiv : the preprint server for biology · 2023Article
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
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- Unique Properties of Apicomplexan Mitochondria.Annual review of microbiology · 2023Review
- Propensity of selecting mutant parasites for the antimalarial drug cabamiquine.Nature communications · 2023Article
- Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.Microbiology spectrum · 2023Article
- Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome.Cell chemical biology · 2023Article
- Current and emerging target identification methods for novel antimalarials.International journal for parasitology. Drugs and drug resistance · 2022Review
- Genome-wide functional screening of drug-resistance genes in Plasmodium falciparum.Nature communications · 2022Article
- Synthesis, Anti-Plasmodial Activities, and Mechanistic Insights of 4-Aminoquinoline-Triazolopyrimidine Hybrids.ACS medicinal chemistry letters · 2022Article
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Malaria is one of the most challenging human infectious diseases, and both prevention and control have been hindered by the development of Plasmodium falciparum resistance to existing therapies. Several new compounds with novel mechanisms are in clinical development for the treatment of malaria, including DSM265, an inhibitor of Plasmodium dihydroorotate dehydrogenase. To explore the mechanisms by which resistance might develop to DSM265 in the field, we selected for DSM265-resistant P. falciparum parasites in vitro. Any of five different amino acid changes led to reduced efficacy on the parasite and to decreased DSM265 binding to P. falciparum DHODH. The DSM265-resistant parasites retained full sensitivity to atovaquone. All but one of the observed mutations were in the DSM265 binding site, and the remaining C276F was in the adjacent flavin cofactor site. The C276F mutation was previously identified in a recrudescent parasite during a Phase IIa clinical study. We confirmed that this mutation (and the related C276Y) accounted for the full level of observed DSM265 resistance by regenerating the mutation using CRISPR/Cas9 genome editing. X-ray structure analysis of the C276F mutant enzyme showed that conformational changes of nearby residues were required to accommodate the larger F276 residue, which in turn led to a restriction in the size of the DSM265 binding pocket. These findings underscore the importance of developing DSM265 as part of a combination therapy with other agents for successful use against malaria.
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