Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations

Musset, Lise; Bouchaud, Olivier; Matheron, Sophie; Massias, Laurent; Bras, J. Le

doi:10.1016/j.micinf.2006.07.011

Cited by 104 publications

(102 citation statements)

References 14 publications

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“…Atovaquone is currently used in combination with proguanil for the treatment of uncomplicated malaria and as a prophylactic agent (36,37). Clinical resistance to atovaquone is known to arise from mutations of cyt bc 1 (38)(39)(40). One of the most prominent mutations is at position 268 (Y268S), which reduces atovaquone binding and catalytic turnover (34,41).…”

Section: Challenges and Current State Of Malaria Drug Developmentmentioning

confidence: 99%

Current therapies and future possibilities for drug development against liver-stage malaria

Raphemot¹,

Posfai²,

Derbyshire³

2016

Journal of Clinical Investigation

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Section: Challenges and Current State Of Malaria Drug Developmentmentioning

confidence: 99%

Current therapies and future possibilities for drug development against liver-stage malaria

Raphemot¹,

Posfai²,

Derbyshire³

2016

Journal of Clinical Investigation

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“…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

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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.

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“…Unfortunately, high rates of recrudescent infection and treatment failure were seen after anti-malarial use of atovaquone alone [6], and treatment failures after atovaquone-proguanil combination therapy (Malarone®) were soon evident [7,8] despite only limited worldwide anti-malarial use. The rapid development and the diversity of atovaquone-resistant phenotypes and genotypes (perhaps a consequence of its mechanism of action [9]), the parallel evolution of resistance-encoding mutations [10] and their appearance with or without atovaquone exposure [11] in dispersed geographic locations, all indicate the strong propensity for atovaquone resistance.…”

Section: Introductionmentioning

confidence: 99%

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Smilkstein

Forquer

Kanazawa

et al. 2008

Molecular and Biochemical Parasitology

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Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc 1 complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc 1 inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc 1 complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc 1 inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc 1 as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.Unlike most other eukaryotic cells, Plasmodia do not rely on mitochondrial electron transport for energy production. Nonetheless, inhibition of cyt bc 1 complex electron transport is normally lethal to the parasite, presumably by interruption of essential links to de novo pyrimidine biosynthesis, via dihydroorotate dehydrogenase (DHODH), and to maintenance of the mitochondrial membrane potential. Although these interrelationships determine the viability of the parasite and our ability to reduce that viability, they are only generally understood. Review of Plasmodial electron transport and cyt bc 1 complex function are beyond the scope of this report, but in-depth discussions are available [1][2][3].The anti-malarial drug atovaquone occupies the quinol oxidase (Q o ) site of mitochondrial cyt b, inhibiting electron flux through the cyt bc 1 complex (ubiquinol:cytochrome c oxidoreductase or complex III) and collapsing mitochondrial membrane potential with a potency 1000-fold greater in Plasmodium than mammalian cells [4,5]. Unfortunately, high rates of recrudescent infection and treatment failure were seen after anti-malarial use of atovaquone alone [6], and treatment failures after atovaquone-proguanil combination therapy (Malarone®) were soon evident [7,8] despite only limited worldwide anti-malarial use. The rapid development and the diversity of atovaquone-resistant phenotypes and genotypes (perhaps a consequence of its mechanism of action [9]), the parallel evolution of resistance-encoding mutations [10] and their appearance with or without atovaquone exposure [11] in dispersed geographic locations, all indicate the strong propensity for atovaquone resistance. The hope that this risk can be overcome by appropriate combination therapy or by novel inhibitors continues to drive efforts to discover and develop cyt bc 1 inhibitor anti-malarials [12].Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that ...

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Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations

Cited by 104 publications

References 14 publications

Current therapies and future possibilities for drug development against liver-stage malaria

Current therapies and future possibilities for drug development against liver-stage malaria

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

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

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