title: 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.
authors.affiliation: School of Life Sciences, University of Nottingham University Park, Nottingham NG7 2RD, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Moreno-Martinez
authors.affiliation: School of Life Sciences, University of Nottingham University Park, Nottingham NG7 2RD, UK.
authors.forename: Cindy
authors.initials: C
authors.lastname: Vallieres
authors.affiliation: School of Life Sciences, University of Nottingham University Park, Nottingham NG7 2RD, UK.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Holland
authors.affiliation: School of Life Sciences, University of Nottingham University Park, Nottingham NG7 2RD, UK.
authors.forename: Simon V
authors.initials: SV
authors.lastname: Avery
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D005658:Fungi / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D012232:Rhizoctonia / Q000187:drug effects; D013431:Sulfates / Q000378:metabolism; D020068:Zygosaccharomyces / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000935:Antifungal Agents; D013431:Sulfates