The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials.

Cindy Vallières,Simon V Avery

doi:10.1128/aac.00459-17

Cindy Vallières, Simon V Avery

Open Access

https://doi.org/10.1128/aac.00459-17

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Abstract

ABSTRACTTo 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 Medicines for Malaria Venture (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 a Saccharomyces cerevisiae 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 synergized 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.

Highlights

To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed
The 400 compounds comprising the Malaria Box were screened for growth inhibition of the yeast model Saccharomyces cerevisiae
With increased recrudescence of Plasmodium isolates resistant to current antimalarials, there is an urgent need for new drugs with broad therapeutic potential and new mechanisms of action to fight against malaria

Summary

Introduction

To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Several groups of investigators have identified resistance mutations in Plasmodium falciparum ATP4 (PfATP4), a Naϩ/Hϩ-ATPase regulating parasite Naϩ, after exposure of Plasmodium spp. to diverse ranges of new agents [5,6,7]. It is still unclear why PfATP4 appears to be a resistance marker for so many recently discovered drugs other transporters such as the P. falciparum chloroquine (CQ) resistance transporter and September 2017 Volume 61 Issue 9 e00459-17. Antibiotics such as aminoglycosides that act via mRNA mistranslation have proven very effective against bacteria [26]

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