Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis
Journal Title
Nat Microbiol
Publication Type
Journal Article
Abstract
Malaria control is heavily dependent on chemotherapeutic agents for disease prevention and drug treatment. Defining the mechanism of action for licensed drugs, for which no target is characterized, is critical to the development of their second-generation derivatives to improve drug potency towards inhibition of their molecular targets. Mefloquine is a widely used antimalarial without a known mode of action. Here, we demonstrate that mefloquine is a protein synthesis inhibitor. We solved a 3.2 A cryo-electron microscopy structure of the Plasmodium falciparum 80S ribosome with the (+)-mefloquine enantiomer bound to the ribosome GTPase-associated centre. Mutagenesis of mefloquine-binding residues generates parasites with increased resistance, confirming the parasite-killing mechanism. Furthermore, structure-guided derivatives with an altered piperidine group, predicted to improve binding, show enhanced parasiticidal effect. These data reveal one possible mode of action for mefloquine and demonstrate the vast potential of cryo-electron microscopy to guide the development of mefloquine derivatives to inhibit parasite protein synthesis.
Publisher
Springer Nature
WEHI Research Division(s)
Chemical Biology; Infection And Immunity
PubMed ID
28288098
NHMRC Grants
NHMRC/1024678
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-04-12 10:42:28
Last Modified: 2017-04-12 12:11:44
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