Synergy and selectivity of antifungal small molecule combinations

While synergistic small molecule combinations are often sought for increased efficacy, the selectivity of antimicrobial compound combinations is also paramount to drug therapy. Using the yeast model organisms S. cerevisiae and C. albicans, we conducted in vitro checkerboard assays for drug interactions of all pairwise combinations of 12 antifungals. We assessed the concavity of isobolograms for growth inhibition as a metric for drug interactions. We found that drug interactions were significantly conserved between these species despite varied concentration-response relationships of single drugs. We developed a metric, the fractional selectivity index, which indicates the relative growth of two cell types in any given ratio of a drug combination. Based on this analysis, we found drug regimens with increased selectivity for growth inhibition of one yeast species relative to another. Our analysis suggests a framework for discovering fixed-dose drug combinations with increased efficacy and selectivity for specific pathogens