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Diverse chemotypes disrupt ion homeostasis in the malaria parasite
Author(s) -
Lehane Adele M.,
Ridgway Melanie C.,
Baker Eileen,
Kirk Kiaran
Publication year - 2014
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12765
Subject(s) - parasite hosting , biology , plasmodium falciparum , cytosol , chemotype , malaria , mechanism of action , biochemistry , microbiology and biotechnology , immunology , in vitro , enzyme , botany , world wide web , computer science , essential oil
Summary The antimalarial spiroindolones disrupt P lasmodium falciparum Na + regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP 4, a parasite plasma membrane P ‐type ATP ase postulated to export Na + and import H + equivalents. Here, we screened the 400 antiplasmodial compounds of the open access ‘ M alaria B ox’ for their effects on parasite ion regulation. Twenty eight compounds affected parasite Na + and pH regulation in a manner consistent with PfATP 4 inhibition. Six of these, with chemically diverse structures, were selected for further analysis. All six showed reduced antiplasmodial activity against spiroindolone‐resistant parasites carrying mutations in pfatp4 . We exposed parasites to incrementally increasing concentrations of two of the six compounds and in both cases obtained resistant parasites with mutations in pfatp4 . The finding that diverse chemotypes have an apparently similar mechanism of action indicates that PfATP 4 may be a significant Achilles' heel for the parasite.