The use of drug combinations is becoming increasingly important in the treatment of viral, bacterial, and parasitic infections. While some of the therapeutic cocktails in use today consist of drugs that are also effective individually, therapies consisting of compounds that only act in synergy might provide useful benefits. Benefits could include a decrease in pathogen mutation rate and a reduction in side effects due to lower drug dosage. We describe an efficient screening approach aimed at the systematic exploration of drug synergy effects in fungi. A commercially available collection of 15,136 drug-like molecules was screened in a liquid culture assay for activity against haploid Saccharomyces cerevisiae. In this library, compound C239-0032 was found to be the most potent antifungal agent with an IC50 of 20 uM. The liquid culture screen was repeated in the presence of a sub-lethal dose of C239-0032 (10 uM) to identify molecules which synergize with C239-0032 to produce a synthetically lethal effect. We identified 41 compounds that are toxic to yeast only in combination with C239-0032 under the conditions of the assay. The most potent combinations identified in this study will be tested at various concentrations on Candida albicans or other pathogenic strains of yeast.

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