Functional Cloning of the Miltefosine Transporter

Pérez-Victoria, F. Javier; Gamarro, Francisco; Ouellette, Marc; Castanys, Santiago

doi:10.1074/jbc.m308352200

Cited by 186 publications

(127 citation statements)

References 37 publications

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“…positions 1259 and 2567, previously reported to be associated with LbMT loss of function (9), and at position 630 analyzed in L. donovani strains isolated from patients with VL and PKDL who relapsed after treatment with miltefosine (19) revealed no association between these SNPs and the resistance phenotype of the clinical strains in our study or genetic variations between strains isolated before treatment and at treatment failure from the same patient (Fig. 5).…”

Section: In Vitro Susceptibility Of Promastigote and Amastigote Stagecontrasting

confidence: 42%

“…The presence of C1259A (T420N) and T2567C (L856P) polymorphisms in the LbMT gene, previously reported to be associated with experimentally derived miltefosine resistance (9), and G630A (W210*) analyzed in VL and post-kala-azar dermal leishmaniasis (PKDL) strains of L. donovani (19) were characterized by sequence analysis of PCR products. Total DNA was extracted from logarithmic-phase promastigotes using a DNeasy blood and tissue kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Single-nucleotide changes in the transporter protein LdMT have been shown to confer resistance to miltefosine (9). Moreover, such mutations are readily selected by incremental in vitro exposure of promastigotes to miltefosine and confer the resistant phenotype on the amastigote stage (9).…”

mentioning

confidence: 99%

“…Moreover, such mutations are readily selected by incremental in vitro exposure of promastigotes to miltefosine and confer the resistant phenotype on the amastigote stage (9). Leishmania braziliensis strains evaluated in vitro for susceptibility to miltefosine have generally demonstrated lower susceptibility than L. donovani; this difference has been attributed to lower expression of the miltefosine transporter complex, LbMT/LbRos3, in the plasma membrane of L. braziliensis (8).…”

mentioning

confidence: 99%

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Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species

Obonaga

Fernández

Valderrama

et al. 2014

Antimicrob Agents Chemother

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Treatment failure and parasite drug susceptibility in dermal leishmaniasis caused by Leishmania (Viannia) species are poorly understood. Prospective evaluation of drug susceptibility of strains isolated from individual patients before drug exposure and at clinical failure allows intrinsic and acquired differences in susceptibility to be discerned and analyzed. To determine whether intrinsic susceptibility or loss of susceptibility to miltefosine contributed to treatment failure, we evaluated the miltefosine susceptibility of intracellular amastigotes and promastigotes of six Leishmania (Viannia) braziliensis and six Leishmania (Viannia) panamensis strains isolated sequentially, at diagnosis and treatment failure, from two children and four adults >55 years old with concurrent conditions. Four patients presented only cutaneous lesions, one had mucosal disease, and one had disseminated mucocutaneous disease. Expression of the Leishmania drug transporter genes abca2, abca3, abcc2, abcc3, abcg4, abcg6,

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Section: In Vitro Susceptibility Of Promastigote and Amastigote Stagecontrasting

confidence: 42%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species

Obonaga

Fernández

Valderrama

et al. 2014

Antimicrob Agents Chemother

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“…Resistance to pentamidine could be related to the loss of the drug transporter PRP1 in the plasmatic membrane [56][57][58] or to lower accumulation in the mitochondrion thus facilitating its efflux [59]. Data on the mechanisms of miltefosine resistance come from laboratory manipulated strains showing that the overexpression of the P-glycoprotein efflux pump or the dysfunction of two proteins LdMT/LdRos3 that are necessary for its uptake, have been involved [60,61]. Reports of lack of response to pentavalent antimony appeared in the 1970s and now this situation is wellrooted in Bihar-India and south-east Nepal.…”

Section: Resistance To Antileishmanial Drugsmentioning

confidence: 99%

Development of new antileishmanial drugs – current knowledge and future prospects

Pape

2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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Leishmaniasis is a protozoan vector borne disease prevalent throughout the world and present in at least 88 countries. The parasite is transmitted by infected phlebotomine sandfly bites. While conventional therapies i.e. pentavalent antimonials, amphotericin B and pentamidine continue to play a major role, it is evident that new drugs or strategies must circumvent the limitations, such as a long-term parenteral administration, toxicity, the high cost in endemic countries and the emergence of resistance, that prevail. One of the most promising drugs is miltefosine, a new oral, approved alkylphospholipid for visceral leishmaniasis with only slight adverse effects. Although we have now this recent and encouraging advance, there is still a need to develop safe, efficient and affordable new treatments for the different clinical forms that exist. This review summarises conventional therapy and the current efforts in the discovery of drugs to treat leishmaniasis with the emphasis on drug combinations to enhance efficiency and prevent the emergence of resistance, the investigation of natural products with the objective of offering new bioactive chemical structures and the development of novel antileishmanial targets.

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