The role of ATP-binding cassette (ABC) proteins in protozoan parasites

Sauvage, Virginie; Aubert, Dominique; Escotte-Binet, Sandie; Villena, Isabelle

doi:10.1016/j.molbiopara.2009.05.005

Cited by 91 publications

(110 citation statements)

References 121 publications

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“…The role of ABC transporters in resistance to different compounds has been studied previously (5,(19)(20)(21). As mentioned above, the Leishmania LABCG2 transporter is involved in the PS externalization required for macrophage infection (10).…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…The P. falciparum multidrug resistance gene (pfmdr1) encodes an ATP-binding cassette protein called P-glycoprotein homolog 1 (Pgh1), which is located on the parasite food vacuole membrane (6) and functions as a transporter (8). The transporter function of Pgh1 couples ATP hydrolysis with solute import into the food vacuole (9). The pfmdr1 gene has been identified as a possible modulator of resistance to a number of antimalarials (10), and the Pgh1 protein has also been implicated as a specific target of antimalarial drugs, such as MFQ (11).…”

mentioning

confidence: 99%

“…Substantial data support a relationship between the pfmdr1 gene and MFQ resistance both in vitro and in vivo (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Specifically, an abundance of in vitro and clinical data link higher pfmdr1 gene copy number and expression with reduced parasite susceptibility to drugs such as quinine (QN), MFQ, and, more recently, artemisinin (9,12,13,16,(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

Mefloquine Exposure Induces Cell Cycle Delay and Reveals Stage-Specific Expression of the pfmdr1 Gene

Bohorquez

Juliano

Kim

et al. 2013

Antimicrob Agents Chemother

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c Drug-resistant Plasmodium falciparum malaria is a major public health problem. An elevated pfmdr1 gene copy number (CN) is known to decrease parasite sensitivity to the commonly used antimalarial mefloquine (MFQ). To understand the relationship between pfmdr1 CN and mefloquine resistance, we evaluated pfmdr1 transcript levels in three P. falciparum strains with different CNs in the presence and absence of MFQ. Parasite strains with multiple pfmdr1 gene copies exhibited higher relative transcript levels than single-copy parasites, and MFQ induced pfmdr1 expression above the levels without treatment in all three strains evaluated. Concomitant morphology analyses of the sampled cultures revealed that MFQ treatment of synchronized ring-stage parasites induced a delay in parasite maturation through the intraerythrocytic cycle. pfmdr1 expression peaks in the ring stage, and MFQ could be causing increased transcription by delaying parasite maturation. However, pretreatment with mefloquine did not affect the artemisinin in vitro half-maximal inhibitory concentration (IC 50 ). These results suggest that MFQinduced increases in pfmdr1 expression are the direct result of the maturation delay at the ring stage but that this change in expression does not affect the antimalarial activity of artemisinin.

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“…Cryptosporidium is resistant to conventional antiparasitic chemotherapies such as antifolates; several drug targets are either absent or highly divergent in the parasite (5). In addition, Cryptosporidium contains many putative drug efflux transporters, which may also protect the parasite (6). Drug development is further impeded by the inability to continuously culture Cryptosporidium in vitro.…”

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confidence: 99%

Prodrug Activation by Cryptosporidium Thymidine Kinase

Sun

Sharling

Muthalagi

et al. 2010

Journal of Biological Chemistry

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Cryptosporidium spp. cause acute gastrointestinal disease that can be fatal for immunocompromised individuals. These protozoan parasites are resistant to conventional antiparasitic chemotherapies and the currently available drugs to treat these infections are largely ineffective. Genomic studies suggest that, unlike other protozoan parasites, Cryptosporidium is incapable of de novo pyrimidine biosynthesis. Curiously, these parasites possess redundant pathways to produce dTMP, one involving thymidine kinase (TK) and the second via thymidylate synthase-dihydrofolate reductase. Here we report the expression and characterization of TK from C. parvum. Unlike other TKs, CpTK is a stable trimer in the presence and absence of substrates and the activator dCTP. Whereas the values of k cat ‫؍‬ 0.28 s ؊1 and K m,ATP ‫؍‬ 140 M are similar to those of human TK1, the value of K m (thymidine) ‫؍‬ 48 M is 100-fold greater, reflecting the abundance of thymidine in the gastrointestinal tract. Surprisingly, the antiparasitic nucleosides AraT, AraC, and IDC are not substrates for CpTK, indicating that Cryptosporidium possesses another deoxynucleoside kinase. Trifluoromethyl thymidine and 5-fluorodeoxyuridine are good substrates for CpTK, and both compounds inhibit parasite growth in an in vitro model of C. parvum infection. Trifluorothymidine is also effective in a mouse model of acute disease. These observations suggest that CpTK-activated pro-drugs may be an effective strategy for treating cryptosporidiosis.

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The role of ATP-binding cassette (ABC) proteins in protozoan parasites

Cited by 91 publications

References 121 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

Mefloquine Exposure Induces Cell Cycle Delay and Reveals Stage-Specific Expression of the pfmdr1 Gene

Prodrug Activation by Cryptosporidium Thymidine Kinase

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