Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis

Wilson Wong, Xiao Chen Bai, Brad E. Sleebs, Tony Triglia, Alan Brown, Jennifer K. Thompson, Katherine E. Jackson, Eric Hanssen, Danushka S. Marapana, Israel S. Fernandez, Stuart A. Ralph, Alan F. Cowman, Sjors H.W. Scheres, Jake Baum

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 Å 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.

Original languageEnglish (US)
Article number17031
JournalNature Microbiology
Volume2
DOIs
StatePublished - Mar 13 2017

Fingerprint

Mefloquine
Plasmodium falciparum
Ribosomes
Cryoelectron Microscopy
Parasites
Proteins
Pharmaceutical Preparations
Protein Synthesis Inhibitors
GTP Phosphohydrolases
Antimalarials
Mutagenesis
Malaria

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis. / Wong, Wilson; Bai, Xiao Chen; Sleebs, Brad E.; Triglia, Tony; Brown, Alan; Thompson, Jennifer K.; Jackson, Katherine E.; Hanssen, Eric; Marapana, Danushka S.; Fernandez, Israel S.; Ralph, Stuart A.; Cowman, Alan F.; Scheres, Sjors H.W.; Baum, Jake.

In: Nature Microbiology, Vol. 2, 17031, 13.03.2017.

Research output: Contribution to journalArticle

Wong, W, Bai, XC, Sleebs, BE, Triglia, T, Brown, A, Thompson, JK, Jackson, KE, Hanssen, E, Marapana, DS, Fernandez, IS, Ralph, SA, Cowman, AF, Scheres, SHW & Baum, J 2017, 'Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis', Nature Microbiology, vol. 2, 17031. https://doi.org/10.1038/nmicrobiol.2017.31
Wong, Wilson ; Bai, Xiao Chen ; Sleebs, Brad E. ; Triglia, Tony ; Brown, Alan ; Thompson, Jennifer K. ; Jackson, Katherine E. ; Hanssen, Eric ; Marapana, Danushka S. ; Fernandez, Israel S. ; Ralph, Stuart A. ; Cowman, Alan F. ; Scheres, Sjors H.W. ; Baum, Jake. / Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis. In: Nature Microbiology. 2017 ; Vol. 2.
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