A novel ATP‐binding cassette transporter from <i>Leishmania</i> is involved in transport of phosphatidylcholine analogues and resistance to alkyl‐phospholipids

Castanys-Muñoz, Esther; Alder-Baerens, Nele; Pomorski, Thomas; Gamarro, Francisco; Castanys, Santiago

doi:10.1111/j.1365-2958.2007.05653.x

Cited by 88 publications

(79 citation statements)

References 39 publications

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“…We analyzed the profile of resistance to different leishmanicidal drugs, including Sb III , amphotericin B, miltefosine, pentamidine, and sitamaquine, and other compounds such as As III , tafenoquine, primaquine, chloroquine, daunomycin, mefloquine, quinine, perifosine, and vinblastine ( Table 1). As described previously, many of them are probably transported by other Leishmania ABCs (5,13,14,28,29). The results showed that promastigotes overexpressing LABCG2 were ϳ6-and 7-fold more resistant to As III and Sb III , respectively, than the control line (pUCNEO) ( Table 1), suggesting that these metal ions could be substrates for the LABCG2 transporter, as previously described for MRPA and ABCI4 (3,5).…”

Section: Resultssupporting

confidence: 57%

“…We also observed that overexpression of LABCG2 did not affect susceptibility to other metal ions such as Cd II , Co II , and Cu II ( Table 2). Contrary to other members of the Leishmania ABCG subfamily such as LABCG4 and LABCG6, LABCG2 does not confer resistance to the alkyl-phospholipids miltefosine and perifosine or the aminoquinolines sitamaquine and chloroquine (13,14). Furthermore, the LABCG2 line "cured" for plasmid pUCNEO-LABCG2 (LABCG2rev) by maintaining the parasites in culture without drug selection for 3 months (LABCG2rev 90D) showed a susceptibility phenotype similar to that of the control line (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…LABCG2 belongs to the same subfamily as mammalian ABCG2, a well-characterized PS transporter (22) that also pumps drugs conferring a multidrug-resistant (MDR) phenotype in cancer cells (23,24). Other Leishmania ABCG proteins, such as LABCG4 and LABCG6, have been described to be involved in phospholipid transport (phosphatidylcholine analogues) and drug resistance (alkyl-phospholipids) (13,14). However, the role of the LABCG2 transporter in drug resistance has not yet been elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…In Leishmania, LABCG4 and LABCG6 transporters have been involved in phosphatidylcholine transport and also confer resistance to different drugs, including miltefosine (13,14). Considering that some ABC transporters present pleiotropic activity in response to therapeutic xenobiotics, we focused on the role of the Leishmania LABCG2 transporter in drug resistance.…”

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confidence: 99%

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The LABCG2 Transporter from the Protozoan Parasite Leishmania Is Involved in Antimony Resistance

Perea

Manzano

Castanys

et al. 2016

Antimicrob Agents Chemother

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Treatment for leishmaniasis, which is caused by Leishmania protozoan parasites, currently relies on a reduced arsenal of drugs. However, the significant increase in the incidence of drug therapeutic failure and the growing resistance to first-line drugs like antimonials in some areas of Northern India and Nepal limit the control of this parasitic disease. Understanding the molecular mechanisms of resistance in Leishmania is now a matter of urgency to optimize drugs used and to identify novel drug targets to block or reverse resistant mechanisms. Some members of the family of ATP-binding cassette (ABC) transporters in Leishmania have been associated with drug resistance. In this study, we have focused our interest to characterize LABCG2's involvement in drug resistance in Leishmania. Leishmania major parasites overexpressing the ABC protein transporter LABCG2 were generated in order to assess how LABCG2 is involved in drug resistance. Assays of susceptibility to different leishmanicidal agents were carried out. Analysis of the drug resistance profile revealed that Leishmania parasites overexpressing LABCG2 were resistant to antimony, as they demonstrated a reduced accumulation of Sb III due to an increase in drug efflux. Additionally, LABCG2 was able to transport thiols in the presence of Sb III . Biotinylation assays using parasites expressing LABCG2 fused with an N-terminal green fluorescent protein tag revealed that LABCG2 is partially localized in the plasma membrane; this supports data from previous studies which suggested that LABCG2 is localized in intracellular vesicles that fuse with the plasma membrane during exocytosis. In conclusion, Leishmania LABCG2 probably confers antimony resistance by sequestering metal-thiol conjugates within vesicles and through further exocytosis by means of the parasite's flagellar pocket.

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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The LABCG2 Transporter from the Protozoan Parasite Leishmania Is Involved in Antimony Resistance

Perea

Manzano

Castanys

et al. 2016

Antimicrob Agents Chemother

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“…In order to explore the relationship between in vitro susceptibility to miltefosine and drug transporters potentially involved in miltefosine transport and multidrug resistance, we evaluated the gene expression profile of the miltefosine transporter LbMT, the multidrug resistance transporters ABCC2 and ABCC3, and the lipid transporters ABCA2, ABCA3, ABCG4, and ABCG6 based on the biochemical homology of miltefosine and phosphatidylcholine and evidence that ABCG4 (17) and ABCG6 (18) are involved in experimentally derived miltefosine resistance.…”

Section: Methodsmentioning

confidence: 99%

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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Terpenoids from Maytenus Species and Assessment of Their Reversal Activity against a Multidrug‐Resistant Leishmania tropica Line

Kennedy

Llanos

Castanys

et al. 2011

Chemistry & Biodiversity

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The phytochemical analysis of the root bark extracts of the Chilean Maytenus, M. chubutensis, and M. magellanica (Celastraceae), led to the isolation of one phenolic nortriterpene, 1, and one diterpene with a nor-ent-kaurene skeleton, 2. In addition, four known compounds were isolated, among which compound 3 has been isolated for the first time from a natural source. Their structures were elucidated by spectroscopic methods, including 1D- and 2D-NMR (COSY, ROESY, HSQC, and HMBC) experiments, comparison with data reported in the literature, and chemical correlations. The isolated compounds were assayed for their reversal activity against a multidrug-resistant Leishmania tropica line, overexpressing a P-glycoprotein related transporter. Compound 1 showed moderate multidrug-resistance reversal activity.

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A novel ATP‐binding cassette transporter from Leishmania is involved in transport of phosphatidylcholine analogues and resistance to alkyl‐phospholipids

Cited by 88 publications

References 39 publications

The LABCG2 Transporter from the Protozoan Parasite Leishmania Is Involved in Antimony Resistance

The LABCG2 Transporter from the Protozoan Parasite Leishmania Is Involved in Antimony Resistance

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

Terpenoids from Maytenus Species and Assessment of Their Reversal Activity against a Multidrug‐Resistant Leishmania tropica Line

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