Novel, Synergistic Antifungal Combinations that Target Translation Fidelity

Abstract

There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone.

Trans-cinnamic acid and Xenorhabdus szentirmaii metabolites synergize the potency of some commercial fungicides

“…Synergy between fungicidal agents has been observed previously (Moreno-Martinez et al, 2015). For example, Baider and Cohen (2003) reported BABA (DL-3-aminobutyric acid) and the protectant fungicide mancozeb were more effective than either agent applied alone for controlling late blight (Phytophthora infestans) in potato and tomato, and downy mildew (Pseudoperonospora cubensis) in cucumber.…”

“…Combined application of different anti-fungal compounds can result in synergism resulting in improved efficacy and reduced potential for development of resistance (Moreno-Martinez et al, 2015). However, combination of pesticidal agents can also result in additive or antagonistic interactions (Shapiro-Ilan et al, 2004, 2016.…”

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

“…Paromomycin is known to cause mRNA mistranslation via ribosome binding ( 26 , 30 ) and has been applied successfully previously to discover mistranslation-based action of other agents ( 29 ). Synergy is evident where a growth effect is significantly stronger with combined drugs than from simple addition of their individual effects, indicating that the compounds target a common process ( 31 ). Each drug was supplied at just subinhibitory concentrations, and growth inhibition was calculated after 15 h. Four of the MMV drugs most active against yeast were tested for synergy ( Fig.…”

“…Due to its essentiality at all stages of the parasite life cycle, protein synthesis could be an important antimalarial drug target. Synergistic drug combinations that target specifically the fidelity of protein synthesis (in fungi) have been described previously ( 31 ). These combinations consisted of an aminoglycoside antibiotic and a sulfate transport inhibitor and produced synergistic inhibition against target organisms but not mammalian cells.…”

Proteomics Analysis for Amino Acid Misincorporation Detection: Mini Review

“…The F-luc has a series of inactivating mutations at a codon (L529) site that encodes an essential lysine residue, permitting monitoring gain of function activity of F-luc caused by Lys misincorporation at the various mutant codons [8]. This approach was used and adapted by other groups and became widely used by the scientific community [25,39]. Javid and co-workers inactivated R-luc, instead of F-luc, by mutating the active site to detect and quantify Glu and Asp misincorporations at Gln and Asn codons in mycobacteria [25].…”