Distinguishing Multicellular from Unicellular Sources of Antifungal Resistance

Multicellular drug resistance is observed in nature and in the clinic in biofilms, flocs, clumps, and tumors. Currently, mechanistic complexity hinders reliable differentiation between unicellular and multicellular sources of drug resistance. Here, we develop a general pipeline for mechanistic drug response interpretation based on growth curve analysis and modeling for two Saccharomyces cerevisiae genetic backgrounds: TBR1 (multicellular, clumping wild-type and unicellular AMN1 deletion mutant) and BY4742 (unicellular wild-type and unicellular AMN1 deletion mutant). The strains in each pair are genetically identical, except for an AMN1 gene deletion. The TBR1 strains represent the effects of both clumping and AMN1 deletion, while the BY4742 strains represent unicellular AMN1 effects. Quantitative analysis and computational modeling of drug-dependent growth curve changes could differentiate between multicellular versus unicellular AMN1-related effects on drug resistance.