Synergy and Selectivity of Small Molecule Combinations
Molecular Biology, Genetics and Bioengineering Program
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 for all pairwise combinations of 12 antifungals. We assessed the concavity of isobolograms for growth inhibition level as a metric for drug interactions. We found that drug interactions were significantly conserved between these species, despite varied dose-response to single drugs. We developed a metric called the 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 killing of a particular yeast species over the other. Our analysis provides a framework for discovering fixed-dose drug combinations with increased efficacy and selectivity against pathogens.