Structural and Functional Analysis of theLaMDR1Multidrug Resistance Gene inLeishmania amazonensis

Katakura, Ken; Iwanami, Masaki; Ohtomo, Hiroshi; Fujise, Hiroshi; Hashiguchi, Yoshihisa

doi:10.1006/bbrc.1999.0209

Cited by 34 publications

(27 citation statements)

References 27 publications

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“…These include Ldmdr1 in L. donovani (23), Lamdr1 and Lamdr2 in L. amazonensis (21,29), LtpgpA in L. tarentolae (20,22,33), Ltmdr1 in L. tropica (19), Lemdr1 in L. enriettii (11), LmepgpA in L. mexicana (13), LmpgpA in L. major (7), and PEN r in L. major (12). Structurally, they can be grouped into the ABCB (Ldmdr1, Lamdr1, Lamdr2, Ltrmdr1, Lemdr1, and PEN r ) and ABCC (LtpgpA, LmepgpA, and LmpgpA) types.…”

Section: Discussionmentioning

confidence: 99%

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium StiboglucanateResistance in Leishmania

Wong

Chan

Burkett

et al. 2007

Antimicrob Agents Chemother

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Drug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with ϳ3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1 ؊/؊ , LeMDR1 ؉/؉ , and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania.

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Section: Discussionmentioning

confidence: 99%

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium StiboglucanateResistance in Leishmania

Wong

Chan

Burkett

et al. 2007

Antimicrob Agents Chemother

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“…Many protozoan parasites have been found to possess MDR-like genes responsible for the expression of membrane proteins with homology to mammalian Pgp or MRP (6,8,17,18,28,32,33). The typical mammalian MDR membrane pump is made up of two homologous peptide halves, each with an intracellular ATP binding domain and six membrane-spanning domains (1).…”

Section: Discussionmentioning

confidence: 99%

“…Protozoan parasite MDRlike membrane proteins are more variable in their structure than their mammalian counterparts. While some have the predicted Pgp structure (18), others have only one rather than two peptides (17), while others have two peptides but fewer than the total of 12 membrane spanning domains (32). Similarly, while mammalian Pgp and MRP pumps have been shown to play significant transport roles and are important in the development of MDR (1), it has not been possible to definitively ascribe such roles to similar proteins in many of the protozoan parasites (6,32,33).…”

Section: Discussionmentioning

confidence: 99%

Role of P Glycoprotein in the Course and Treatment of Encephalitozoon Microsporidiosis

Leitch

Scanlon

Shaw

et al. 2001

Antimicrob Agents Chemother

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Encephalitozoon microsporidia are obligate intracellular protozoan parasites that proliferate and differentiate within a parasitophorous vacuole inside host cells that are usually epithelial in nature. Isolates of the three species of the Encephalitozoon microsporidia, E. cuniculi, E. hellem, and E. intestinalis, were obtained from AIDS patients and cultured in green monkey (E6) kidney cells. Anti-P-glycoprotein (anti-Pgp) and antimultidrug resistance-associated protein (anti-MRP) monoclonal antibodies were used to probe for multidrug resistance (MDR) pump epitopes and verapamil-or cyclosporin A-and probenecid-modulated intracellular calcein fluorescence were used to assess the expression of Pgp and MRP respectively in uninfected and infected cells. Pgp, but not MRP, was detected immunocytochemically and by verapamil-and cyclosporin A-potentiated intracellular fluorescence in both host cells and parasite developing stages. When an in vitro infection assay was employed, verapamil and cyclosporin A acted as chemosensitizing agents for the antiparasitic drug albendazole. These observations suggest that inhibiting host cell and perhaps parasite MDR pumps may increase the efficacy of antiparasitic agents in these and other microsporidia species.

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“…The PGP-like family includes MDR1, a gene identified in the amplified circular DNA (V-circle) that mediates resistance to hydrophobic drugs, like vinblastine and puromycin, in Leishmania spp. [17][18][19]. Data emerging from the Leishmania Genome Project suggest the presence of additional members of this superfamily [20].…”

Section: Introductionmentioning

confidence: 99%

Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major

Coelho¹,

Beverley

Cotrim³

2003

Molecular and Biochemical Parasitology

122

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Structural and Functional Analysis of theLaMDR1Multidrug Resistance Gene inLeishmania amazonensis

Cited by 34 publications

References 27 publications

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium StiboglucanateResistance in Leishmania

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium StiboglucanateResistance in Leishmania

Role of P Glycoprotein in the Course and Treatment of Encephalitozoon Microsporidiosis

Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major

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