Targeting regulators of cellular circuitry that are crucial for cellular stress responses may provide a powerful strategy for antifungal drug development. This strategy opens up the opportunity for combining stress response inhibitors with current antifungals for treatment of fungal infections. Promising examples of this approach include targeting the molecular chaperone Hsp90 or its downstream effector calcineurin, which are both required for drug resistance and virulence of diverse fungal pathogens8, 55. Given that both of these regulators are highly conserved in humans and have essential functions in mobilizing immune responses, the challenge in exploiting the therapeutic utility of these targets for antifungal therapies hinges on the development of fungal-selective inhibitors56. Our work further supported the role of Cas5 in governing echinocandin tolerance and established that Cas5 enables echinocandin resistance in a strain harboring a mutation in the drug target gene FKS1 (Fig. 3b). As Cas5 lacks an identifiable ortholog in humans22, but is required for drug resistance (Fig. 3b) and virulence in C. albicans 10, 57, it provides an attractive target for antifungal drug development. There is growing support for the feasibility of chemical modulation of transcription factors based on blocking transcription factor dimerization, DNA binding, or the interaction with regulatory proteins58, 59. Elucidating mechanisms that enable remodeling of transcriptional programs that control stress response and virulence traits provides opportunities to expand the antimicrobial target space in this era of antimicrobial resistance.