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The candidate antimalarial drug MMV665909 causes oxygen-dependent mRNA mistranslation and synergises with quinoline-derived antimalarials

Vallieres, Cindy; Avery, Simon V.

Authors

Cindy Vallieres

Simon V. Avery



Abstract

To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the MMV Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with the yeast cell model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen-dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug’s action on translation fidelity being mediated through Rli1. The MMV drug also synergised with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine and primaquine. The data collectively suggest translation-fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate.

Journal Article Type Article
Publication Date Sep 1, 2017
Journal Antimicrobial Agents and Chemotherapy
Print ISSN 0066-4804
Electronic ISSN 1098-6596
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 61
Issue 9
Article Number e00459-17
APA6 Citation Vallieres, C., & Avery, S. V. (2017). The candidate antimalarial drug MMV665909 causes oxygen-dependent mRNA mistranslation and synergises with quinoline-derived antimalarials. Antimicrobial Agents and Chemotherapy, 61(9), https://doi.org/10.1128/AAC.00459-17
DOI https://doi.org/10.1128/AAC.00459-17
Keywords Translation fidelity, Iron-sulphur cluster, Oxidative stress, Medicines for malaria
18 venture, malaria
Publisher URL http://aac.asm.org/content/early/2017/06/20/AAC.00459-17
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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