Prevalence of Plasmodium falciparum cytochrome b gene mutations in isolates imported from Africa, and implications for atovaquone resistance

Berry, Antoine; Senescau, Alice; Lelièvre, Joël; Benoit‐Vical, Françoise; Fabre, Richard; Marchou, B.; Magnaval, Jean-François

doi:10.1016/j.trstmh.2006.02.004

Cited by 26 publications

(17 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Musset et al (2006) [40] genotyped 477 atovaquone-unexposed African P. falciparum isolates and found exclusively wild types. Berry et al (2006) [41] found polymorphisms in 12/135 (8.9%) of unexposed West and Central African isolates; an overall rate which is consistent with ours. Nine were only transitions and therefore 'silent'; only three led to transversions with amino acid changes; again, a rate very to the one presented in this paper.…”

Section: Resultssupporting

confidence: 91%

Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia

Gebru

Hailu

Kremsner

et al. 2006

Malar J

View full text Add to dashboard Cite

Background: Atovaquone is part of the antimalarial drug combination atovaquone-proguanil (Malarone ® ) and inhibits the cytochrome bc 1 complex of the electron transport chain in Plasmodium spp. Molecular modelling showed that amino acid mutations are clustered around a putative atovaquone-binding site resulting in a reduced binding affinity of atovaquone for plasmodial cytochrome b, thus resulting in drug resistance.

show abstract

Section: Resultssupporting

confidence: 91%

Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia

Gebru

Hailu

Kremsner

et al. 2006

Malar J

View full text Add to dashboard Cite

show abstract

“…One major concern regarding the use of cyt bc 1 inhibitors as treatments for malaria is the propensity for Plasmodium drug resistance. [26][27][28] Although atovaquone is the only cyt bc 1 inhibitor in clinical use, atovaquone resistance develops rapidly in the setting of monotherapy. As a result, several highly resistant strains have emerged, including the clinical isolate Tm90-C2B, which contains a Y268S mutation at the cyt b Q o site and is more than 3,000-fold less sensitive to atovaquone.…”

Section: Elq-400 Single-dose Antimalarial Therapymentioning

confidence: 99%

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Stickles

Ting

Morrisey

et al. 2015

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the bloodstage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc 1 (cyt bc 1 ) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc 1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc 1 . Ultimately, ELQ-400 shows that cyt bc 1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc 1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development.

show abstract

“…[309][310][311] However, the prevalence of mutations of the cytochrome b gene that confer resistance to this combination in primary isolates seems to be lower than 1 %. [312][313][314] To shield the atovaquone/ proguanil combination from emerging resistance, it has been successfully combined with artesunate (42) for the treatment of uncomplicated malaria. [315] This combination was also used for the treatment of uncomplicated as well as recrudescent multiple-resistant malaria during pregnancy.…”

Section: Mechanism Of Action and Resistancementioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

View full text Add to dashboard Cite

Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

show abstract

Prevalence of Plasmodium falciparum cytochrome b gene mutations in isolates imported from Africa, and implications for atovaquone resistance

Cited by 26 publications

References 11 publications

Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia

Molecular surveillance of mutations in the cytochrome b gene of Plasmodium falciparum in Gabon and Ethiopia

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Contact Info

Product

Resources

About