ArticleAntimicrobial agents and chemotherapy2014
Emergence of resistance to atovaquone-proguanil in malaria parasites: insights from computational modeling and clinical case reports.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 2 of them syntheses that pooled it.
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Who cites it
22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 52 citations in OpenAlex.
- Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria.The Cochrane database of systematic reviews · 2021Pooled it
- Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis.The Journal of antimicrobial chemotherapy · 2018Pooled it
- Mechanistic perspectives on antimalarial agents: from FDA-approved drugs to next-generation candidates.RSC advances · 2026Review
- Treatment of avian malaria in captive African penguins (International journal of veterinary science and medicine · 2025Article
- Targeting theProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Impact on parasitemia, survival time and pro-inflammatory immune response in mice infected withFrontiers in pharmacology · 2024Article
- A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites.PLoS pathogens · 2023Article
- Amplicon Deep Sequencing Reveals Multiple Genetic Events Lead to Treatment Failure with Atovaquone-Proguanil in Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2023Article
- Article
- Oxidative Stress in Malaria: Potential Benefits of Antioxidant Therapy.International journal of molecular sciences · 2022Review
- 5WBF: a low-cost and straightforward whole blood filtration method suitable for whole-genome sequencing of Plasmodium falciparum clinical isolates.Malaria journal · 2022Article
- A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites.Microbiology spectrum · 2021Article
- Selection of CytochromeAntimicrobial agents and chemotherapy · 2021Article
- Exposure to ambient air causes degradation and decreasedVeterinary parasitology: X · 2020Article
- Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone-proguanil in traveller returning from Congo.Malaria journal · 2020Article
- An Overview of Drug Resistance in Protozoal Diseases.International journal of molecular sciences · 2019Review
- Selection ofProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.Nature medicine · 2017Review
- Current therapies and future possibilities for drug development against liver-stage malaria.The Journal of clinical investigation · 2016Review
- Advanced Molecular Detection of Malarone Resistance.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The usefulness of atovaquone-proguanil (AP) as an antimalarial treatment is compromised by the emergence of atovaquone resistance during therapy. However, the origin of the parasite mitochondrial DNA (mtDNA) mutation conferring atovaquone resistance remains elusive. Here, we report a patient-based stochastic model that tracks the intrahost emergence of mutations in the multicopy mtDNA during the first erythrocytic parasite cycles leading to the malaria febrile episode. The effect of mtDNA copy number, mutation rate, mutation cost, and total parasite load on the mutant parasite load per patient was evaluated. Computer simulations showed that almost any infected patient carried, after four to seven erythrocytic cycles, de novo mutant parasites at low frequency, with varied frequencies of parasites carrying varied numbers of mutant mtDNA copies. A large interpatient variability in the size of this mutant reservoir was found; this variability was due to the different parameters tested but also to the relaxed replication and partitioning of mtDNA copies during mitosis. We also report seven clinical cases in which AP-resistant infections were treated by AP. These provided evidence that parasiticidal drug concentrations against AP-resistant parasites were transiently obtained within days after treatment initiation. Altogether, these results suggest that each patient carries new mtDNA mutant parasites that emerge before treatment but are killed by high starting drug concentrations. However, because the size of this mutant reservoir is highly variable from patient to patient, we propose that some patients fail to eliminate all of the mutant parasites, repeatedly producing de novo AP treatment failures.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.