Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of antimalarial cinchona alkaloids

Authors

Carol E. Griffin, Department of Biological Sciences, Old Dominion University
Jonathan M. Hoke, Department of Biological Sciences, Old Dominion UniversityFollow
Upeka Samarakoon, Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
Junhui Duan, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jianbing Mu, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthFollow
Michael T. Ferdig, Eck Institute for Global Health, Department of Biological Sciences, University of Notre DameFollow
David C. Warhurst, Department of Pathogen Molecular Biology, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine,
Roland Cooper, Department of Natural Sciences and Mathematics, Dominican University of CaliforniaFollow

Document Type

Article

Source

Antimicrobial Agents and Chemotherapy

ISSN

1098-6569

Volume

56

Issue

10

First Page

5356

Last Page

5364

Publication Date

10-2012

Department

Natural Sciences and Mathematics

Abstract

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility of eight clonal lines of P. falciparum derived from the 106/1 strain, each containing a unique pfcrt allele, to four Cinchona stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the Cinchona alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC(50) ratio of (-)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (-) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other Cinchona alkaloids.

Rights

Copyright © 2004 American Society for Microbiology. All rights reserved.

Publisher Statement

Griffin, C. E., Hoke, J. M., Samarakoon, U., Duan, J., Mu, J., Ferdig, M. T., ... & Cooper, R. A. (2012). Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of the antimalarial Cinchona alkaloids. Antimicrobial agents and chemotherapy, AAC-05667.

PubMed ID

22869567