Open AccessMolecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria
Author(s) -
Kathryn J. Wicht,
Sachel Mok,
David A. Fidock
Publication year - 2020
Publication title -
annual review of microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.817
H-Index - 192
eISSN - 1545-3251
pISSN - 0066-4227
DOI - 10.1146/annurev-micro-020518-115546
Subject(s) - plasmodium falciparum , artemisinin , piperaquine , chloroquine , amodiaquine , biology , drug resistance , mefloquine , malaria , multiple drug resistance , atp binding cassette transporter , heme , pharmacology , transporter , virology , biochemistry , microbiology and biotechnology , immunology , gene , enzyme
Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. Plasmodium falciparum parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the P. falciparum chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification. The structure of PfCRT, solved by cryogenic electron microscopy, shows mutations surrounding an electronegative central drug-binding cavity where they presumably interact with drugs and natural substrates to control transport. P. falciparum susceptibility to heme-binding antimalarials is also modulated by overexpression or mutations in the digestive vacuole membrane-bound ABC transporter PfMDR1 ( P. falciparum multidrug resistance 1 transporter). Artemisinin resistance is primarily mediated by mutations in P. falciparum Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and artemisinin activation. Combating drug-resistant malaria urgently requires the development of new antimalarial drugs with novel modes of action.