Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum

Molecular Microbiology
Cecilia P SanchezMichael Lanzer

Abstract

Resistance to several anti-malarial drugs has been associated with polymorphisms within the P-glycoprotein homologue (Pgh-1, PfMDR1) of the human malaria parasite Plasmodium falciparum. Pgh-1, coded for by the gene pfmdr1, is predominately located at the membrane of the parasite's digestive vacuole. How polymorphisms within this transporter mediate alter anti-malarial drug responsiveness has remained obscure. Here we have functionally expressed pfmdr1 in Xenopus laevis oocytes. Our data demonstrate that Pgh-1 transports vinblastine, an established substrate of mammalian MDR1, and the anti-malarial drugs halofantrine, quinine and chloroquine. Importantly, polymorphisms within Pgh-1 alter the substrate specificity for the anti-malarial drugs. Wild-type Pgh-1 transports quinine and chloroquine, but not halofantrine, whereas polymorphic Pgh-1 variants, associated with altered drug responsivenesses, transport halofantrine but not quinine and chloroquine. Our data further suggest that quinine acts as an inhibitor of Pgh-1. Our data are discussed in terms of the model that Pgh-1-mediates, in a variant-specific manner, import of certain drugs into the P. falciparum digestive vacuole, and that this contributes to accumulation of, and su...Continue Reading

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Citations

Nov 3, 2010·Antimicrobial Agents and Chemotherapy·Dorothee BeezMichael Lanzer
Mar 31, 2010·Antimicrobial Agents and Chemotherapy·Marina ChavchichDennis E Kyle
Mar 11, 2009·Antimicrobial Agents and Chemotherapy·Maud HenryBruno Pradines
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Sep 3, 2010·Molecular Microbiology·Jigar J PatelMichael T Ferdig
May 22, 2010·Molecular Microbiology·Alexander RotmannMichael Lanzer
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Oct 24, 2019·ACS Infectious Diseases·Lydia Mata-CanteroMaria G Gomez-Lorenzo

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