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Fungi threaten the security of food supply to human populations on several fronts. They destroy up to 30 % of crop products through disease and spoilage processes, while mycotoxin-producing fungi and opportunistic pathogens endanger food safety. Control of these fungi is vital for improving food security, but current measures are inadequate and further challenges due to human-population growth and climate change are escalating. Investment and innovation in research on strategies to control fungal growth, harnessed through international, inter-disciplinary collaboration across socio-economic boundaries, provides one key to rising to this challenge., (Copyright © 2019 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

A wide range of fungicides (or antifungals) are used in agriculture and medicine, with activities against a spectrum of fungal pathogens. Unfortunately, the evolution of fungicide resistance has become a major issue. Therefore, there is an urgent need for new antifungal treatments. Certain metals have been used for decades as efficient fungicides in agriculture. However, concerns over metal toxicity have escalated over this time. Recent studies have revealed that metals like copper and chromate can impair functions required for the fidelity of protein synthesis in fungi. This occurs through different mechanisms, based on targeting of iron-sulphur cluster integrity or competition for uptake with amino acid precursors. Moreover, chromate at least acts synergistically with other agents known to target translation fidelity, like aminoglycoside antibiotics, causing dramatic and selective growth inhibition of several fungal pathogens of humans and plants. As such synergy allows the application of decreased amounts of metals for effective inhibition, it lessens concerns about nonspecific toxicity and opens new possibilities for metal applications in combinatorial fungicides targeting protein synthesis., (© 2017 Elsevier Ltd. All rights reserved.)

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.

Fungi cause diverse, serious socio-economic problems, including biodeterioration of valuable products and materials that spawns a biocides industry worth ~$11 billion globally. To help combat environmental fungi that commonly colonise material products, this study tested the hypothesis that combination of an approved fungicide with diverse agents approved by the FDA (Food and Drug Administration) could reveal potent combinatorial activities with promise for fungicidal applications. The strategy to use approved compounds lowers potential development risks for any effective combinations. A high-throughput assay of 1280 FDA-approved compounds was conducted to find those that potentiate the effect of iodopropynyl-butyl-carbamate (IPBC) on the growth of Trichoderma virens; IPBC is one of the two most widely used Biocidal Products Regulations–approved fungicides. From this library, 34 compounds in combination with IPBC strongly inhibited fungal growth. Low-cost compounds that gave the most effective growth inhibition were tested against other environmental fungi that are standard biomarkers for resistance of synthetic materials to fungal colonisation. Trifluoperazine (TFZ) in combination with IPBC enhanced growth inhibition of three of the five test fungi. The antifungal hexetidine (HEX) potentiated IPBC action against two of the test organisms. Testable hypotheses on the mechanisms of these combinatorial actions are discussed. Neither IPBC + TFZ nor IPBC + HEX exhibited a combinatorial effect against mammalian cells. These combinations retained strong fungal growth inhibition properties after incorporation to a polymer matrix (alginate) with potential for fungicide delivery. The study reveals the potential of such approved compounds for novel combinatorial applications in the control of fungal environmental opportunists. Key points: • Search with an approved fungicide to find new fungicidal synergies in drug libraries. • New combinations inhibit growth of key environmental fungi on different matrices. • The approach enables a more rapid response to demand for new biocides. [ABSTRACT FROM AUTHOR]

We developed a top-down strategy to characterize an antimicrobial, oxidizing sanitizer, which has diverse proposed applications including surface-sanitization of fresh foods, and with benefits for water resilience. The strategy involved finding quenchers of antimicrobial activity then antimicrobial mode of action, by identifying key chemical reaction partners starting from complex matrices, narrowing down reactivity to specific organic molecules within cells. The sanitizer electrolyzed-water (EW) retained partial fungicidal activity against the food-spoilage fungus Aspergillus niger at high levels of added soils (30–750 mg mL–1), commonly associated with harvested produce. Soil with high organic load (98 mg g–1) gave stronger EW inactivation. Marked inactivation by a complex organics mix (YEPD medium) was linked to its protein-rich components. Addition of pure proteins or amino acids (≤1 mg mL–1) fully suppressed EW activity. Mechanism was interrogated further with the yeast model, corroborating marked suppression of EW action by the amino acid methionine. Pre-culture with methionine increased resistance to EW, sodium hypochlorite, or chlorine-free ozonated water. Overexpression of methionine sulfoxide reductases (which reduce oxidized methionine) protected against EW. Fluoroprobe-based analyses indicated that methionine and cysteine inactivate free chlorine species in EW. Intracellular methionine oxidation can disturb cellular FeS-clusters and we showed that EW treatment impairs FeS-enzyme activity. The study establishes the value of a top-down approach for multi-level characterization of sanitizer efficacy and action. The results reveal proteins and amino acids as key quenchers of EW activity and, among the amino acids, the importance of methionine oxidation and FeS-cluster damage for antimicrobial mode-of-action. [ABSTRACT FROM AUTHOR]

A wide range of fungicides (or antifungals) are used in agriculture and medicine, with activities against a spectrum of fungal pathogens. Unfortunately, the evolution of fungicide resistance has become a major issue. Therefore, there is an urgent need for new antifungal treatments. Certain metals have been used for decades as efficient fungicides in agriculture. However, concerns over metal toxicity have escalated over this time. Recent studies have revealed that metals like copper and chromate can impair functions required for the fidelity of protein synthesis in fungi. This occurs through different mechanisms, based on targeting of iron-sulphur cluster integrity or competition for uptake with amino acid precursors. Moreover, chromate at least acts synergistically with other agents known to target translation fidelity, like aminoglycoside antibiotics, causing dramatic and selective growth inhibition of several fungal pathogens of humans and plants. As such synergy allows the application of decreased amounts of metals for effective inhibition, it lessens concerns about nonspecific toxicity and opens new possibilities for metal applications in combinatorial fungicides targeting protein synthesis. [ABSTRACT FROM AUTHOR]

Individual fungal cells within genetically-uniform populations can exhibit striking phenotypic variability. This phenotypic heterogeneity has been proposed recently to promote the fitness of fungal populations, independently of fitness contributions arising from genetic diversity. Consequently, several major recent studies have been focused on unravelling the physiological and molecular bases for heterogeneity. This article provides an overview of the current state of play in this emerging field, with a focus on heterogeneity in the single-cell yeast Saccharomyces cere-visiae and on the novel methodologies being developed to study heterogeneity. [Copyright &y& Elsevier]