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

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 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.

Mitochondrial Ferredoxin Determines Vulnerability of Cells to Copper Excess

“…In contrast to the observed rescue of Cu sensitivity via overexpression of Yah1 ( Figures 1 B and 1C) or of pro-oxidant action via Rli1 ( Alhebshi et al., 2012 , Laleve et al., 2016 , Vallieres and Avery, 2017 ), increased expression of nonessential FeS proteins is known potentially to exacerbate ROS stress. This is because of the increased pool of labile FeS which, following turnover (e.g., ROS mediated), leads to the accumulation of free Fe and further potential for ROS stress via Fe-catalyzed Fenton chemistry ( Keyer and Imlay, 1996 , Liochev and Fridovich, 1999 ).…”

Novel Combinations of Agents Targeting Translation That Synergistically Inhibit Fungal Pathogens

“…Quinoline-containing compounds are known to provoke reactive oxygen species (ROS) production ( Radfar et al, 2008 ; Tafazoli and O’Brien, 2009 ; Laleve et al, 2016 ). As ROS may in turn promote oxidation of RNA or of proteins involved in translation ( Ling and Soll, 2010 ; Vallieres and Avery, 2017b ), alternative potential causes of mistranslation, we tested whether the synergy between quinine + hygromycin (associated with elevated mistranslation) could be suppressed by the absence of oxygen. However, synergy was slightly enhanced rather than rescued under anaerobic growth conditions ( Figure 9C ).…”

“…One limitation could relate to the apparent drug concentrations needed to control fungal growth, as addressed in the next paragraph. One pertinent point concerning quinine is that common quinine analogs, albeit typically more expensive than quinine, can have much lower effective MICs against fungi ( Table 1 ; Vallieres and Avery, 2017b ).…”

Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals the potential mechanism of action of miltefosine

“…The development of new antifungal drugs raises challenges such as the high costs and the time required for development and licensing of new compounds. To circumvent the slowness and cost of developing new drugs, the screening of chemical libraries and repurposing of drugs that are already commercialized for other purposes is a great opportunity to discover new antifungal compounds (62,64,67,71,(91)(92)(93).…”

“…for development and licensing of new compounds. To circumvent the slowness and cost of developing new drugs, the screening of chemical libraries and repurposing of drugs that are already commercialized for other purposes is a great opportunity to discover new antifungal compounds(62,64,67,71,(91)(92)(93).Here we screened the growth of A. fumigatus in the presence of compounds present in two drug libraries and identified 10 compounds, among them five compounds already known as inhibitors of fungal growth including two azolederivatives (econazole nitrate, and oxiconazole nitrate), fluvastatin, that inhibits ergosterol biosynthesis, and iodoquinol and miltefosine, drugs with an unknown mechanism of action. To our knowledge, the other five identified compounds (mesoridazine, cisapride, indinavir sulfate, enalaprilat, and vincristine sulfate) are novel as antifungal agents and have not been reported before.…”