Fungal infections are a major challenge to medicine and agriculture. Repeated and prophylactic use of antifungals can lead to pathogen cross-resistance to different classes of drugs. The early development of multidrug resistance in pathogenic fungi includes drug tolerance mediated by drug-dependent activation of drug efflux. In Saccharomyces cerevisiae and the fungal pathogen Candida glabrata, xenobiotic sensing motifs in transcription factors upregulate expression of several ATP-binding cassette (ABC) drug efflux pumps. We have therefore considered how drug candidates that trigger or prevent drug resistance could be identified and evaluated during drug discovery. We report a robust and sensitive, S. cerevisiae-based xenobiotic sensing system using the Pdr1 protein as a sensor and an attenuated version of the apoptotic murine BCL2-associated X (BAX) gene as a reporter. A molecular mechanism of attenuation that involves frameshift reversal may be associated with translation coupling and requires further investigation. © FEMS 2019.