Characterisation of atovaquone resistance in Leishmania infantum promastigotes

Cauchetier, E.; Loiseau, Philippe M.; Lehman, Julia S.; Rivollet, D.; Fleury, J; Astier, A.; Deniau, M.; Paul, Muriel

doi:10.1016/s0020-7519(02)00065-6

Cited by 28 publications

(22 citation statements)

References 34 publications

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“…An analogue of ubiquinone, an antimalarial drug atovaquone (2-[trans-4-(4¢-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-hydroxynaphtoquinone), has been demonstrated to be effective against the agents of visceral leishmaniasis, Leishmania donovani (Croft et al 1992), L. chagasi (Jernigan et al1996) and L. infantum (Cauchetier et al 2002). In Plasmodium and Toxoplasma, atovaquone acts as an inhibitor of the cytochrome bc 1 complex, competing with ubiquinol for the substrate binding site in cytochrome b (Syafruddin et al 1999;McFadden et al 2000), and the same mechanism is assumed for Leishmania.…”

Section: Resultsmentioning

confidence: 99%

NADH-ubiquinone oxidoreductase activity in the kinetoplasts of the plant trypanosomatid Phytomonas serpens

González‐Halphen

Maslov

2004

Parasitology Research

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NADH-ubiquinone oxidoreductase activity is present in mitochondrial lysates of Phytomonas serpens. Rotenone at 2-10 microM inhibited the activity 50-75%, indicating that it belongs to respiratory complex I. The activity was also inhibited 50-60% in the presence of 10-30 nM atovaquone suggesting that inhibition of complex I represents a likely mechanism of the known antileishmanial activity of this drug. The complex was partially purified by chromatography on DEAE-Sepharose CL-6B and gel-filtration on Sepharose CL-2B. The NADH:ubiquinone oxidoreductase activity in this preparation was completely inactivated by 20 nM atovaquone. The partially purified complex was present in a low amount and its subunits could not be discerned by staining with Coomassie. However, one of its components, a homologue of the 39 kDa subunit of the bovine complex I, was identified immunochemically in the original lysate and in the partially purified material.

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Section: Resultsmentioning

confidence: 99%

NADH-ubiquinone oxidoreductase activity in the kinetoplasts of the plant trypanosomatid Phytomonas serpens

González‐Halphen

Maslov

2004

Parasitology Research

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“…Atovaquone shows a high activity against several intra-and extracellular protozoa (Araujo et al 1991;Hughes et al 1993;Matsuu et al 2004;Murray and Hariprashad 1996;Cauchetier et al 2002) and, associated with proguanil, is currently used in malaria prophylaxis and treatment (Pelter and Kain 2005;Polhemus et al 2008). From a biopharmaceutical point of view, atovaquone can be classified as a BCS class II, characterised by a high permeability and a low aqueous solubility (Dressman and Reppas 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Other possibilities to increase the atovaquone oral bioavailability have been proposed, including the development of nanosuspensions (Dearn 2000;Nicolaides et al 1999), self-microemulsifying drug delivery systems (Sek et al 2008), liposomes (Cauchetier et al 2000) or polymer nanocapsules (Dalençon et al 1997;Sordet et al 1998;Cauchetier et al 2002). All of these strategies are based on an increment of the specific surface area of the atovaquone particles and/or its solubility in adequate solvents or micelles to facilitate its dispersion in aqueous media.…”

Section: Discussionmentioning

confidence: 99%

Cyclodextrin/poly(anhydride) nanoparticles as drug carriers for the oral delivery of atovaquone

Calvo

Lavandera

Agüeros

et al. 2011

Biomed Microdevices

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The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl--cyclodextrin (HPCD), 2,6-di-O-methyl-β-cyclodextrin (DCMD), randomly methylated-β-cyclodextrin (RMCD) and sulfobuthyl ether-β-cyclodextrin (SBECD).Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes. For the pharmacokinetic studies, ATO formulations were administered orally in rats. Overall, ATO displayed a higher affinity for methylated cyclodextrins than for the other derivatives. However, for in vivo studies, both ATO-DMCD-NP and ATO-HPCD-NP were chosen. These nanoparticle formulations showed more adequate physicochemical properties in terms of size (< 260 nm), drug loading (17.8 and 16.9 g/mg, respectively) and yield (>75%). In vivo, nanoparticle formulations induced higher and more prolonged plasmatic levels of atovaquone than control suspensions of the drug in methylcellulose. Relative bioavailability of ATO when loaded in nanoparticles ranged from 52% (for ATO-HPCD NP) to 71% (for ATO-DMCD NP), whereas for the suspension control formulation the bioavailability was only about 30%. The encapsulation of atovaquone in cyclodextrinspoly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.

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“…Sterol identification by GC-MS. Cauchetier and colleagues successfully identified more than a dozen sterols in logarithmicphase L. infantum promastigotes using GC-MS to analyze sterols extracted with dichloromethane-methanol (22). The compounds identified included ergosterol and its biosynthetic pathway precursors.…”

Section: Resultsmentioning

confidence: 99%

Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

et al. 2013

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The infectious metacyclic promastigotes of Leishmania protozoa establish infection in a mammalian host after they are deposited into the dermis by a sand fly vector. Several Leishmania virulence factors promote infection, including the glycosylphosphatidylinositol membrane-anchored major surface protease (MSP). Metacyclic Leishmania infantum chagasi promastigotes were treated with methyl-beta-cyclodextrin (M␤CD), a sterol-chelating reagent, causing a 3-fold reduction in total cellular sterols as well as enhancing MSP release without affecting parasite viability in vitro. M␤CD-treated promastigotes were more susceptible to complement-mediated lysis than untreated controls and reduced the parasite load 3-fold when inoculated into BALB/c mice. Paradoxically, M␤CD-treated promastigotes caused a higher initial in vitro infection rate in human or murine macrophages than untreated controls, although their intracellular multiplication was hindered upon infection establishment. There was a corresponding larger amount of covalently bound C3b than iC3b on the parasite surfaces of M␤CD-treated promastigotes exposed to healthy human serum in vitro, as well as loss of MSP, a protease that enhances C3b cleavage to iC3b. Mass spectrometry showed that M␤CD promotes the release of proteins into the extracellular medium, including both MSP and MSPlike protein (MLP), from virulent metacyclic promastigotes. These data support the hypothesis that plasma membrane sterols are important for the virulence of Leishmania protozoa at least in part through retention of membrane virulence proteins. Leishmania protozoa shuttle between a mammalian host as intracellular amastigotes and a sand fly vector as flagellated promastigotes. The sand fly acquires amastigote-laden cells during a blood meal. In the sand fly midgut, procyclic promastigotes derived from transformation of amastigotes undergo multiplication and development via intermediate stages, eventually yielding metacyclic promastigotes (1). The infectious metacyclic promastigote is inoculated into a pool of blood in the dermis of a mammalian host formed during a sand fly bite. Parasites are phagocytized by host macrophages, where they transform to amastigotes and multiply in parasitophorous vacuoles. Amastigotes spread to new macrophages at local or disseminated sites, perpetuating the infection and ultimately resulting in asymptomatic infections or symptomatic leishmaniasis (2). Various forms of leishmaniasis are endemic in 88 countries on four continents, leading to approximately two million new cases and 59,000 deaths annually (3).Both host and parasite factors contribute to the success of infection. On one hand, mammalian host environmental risk factors and genetic background influence the clinical manifestations of infection (4). On the other hand, parasite virulence determinants required for disease development include, but are not limited to, the major surface protease (MSP) (also called GP63 or leishmanolysin) and lipophosphoglycan (LPG) (5-8). These two molecules play both overl...

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Characterisation of atovaquone resistance in Leishmania infantum promastigotes

Cited by 28 publications

References 34 publications

NADH-ubiquinone oxidoreductase activity in the kinetoplasts of the plant trypanosomatid Phytomonas serpens

NADH-ubiquinone oxidoreductase activity in the kinetoplasts of the plant trypanosomatid Phytomonas serpens

Cyclodextrin/poly(anhydride) nanoparticles as drug carriers for the oral delivery of atovaquone

Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

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