CO2 potentiates echinocandin efficacy during invasive candidiasis therapy via dephosphorylation of Hsp90 by Ptc2 in condensates.

Carbon dioxide is a signaling cue critical for fungal pathogenesis. Ptc2, a type 2C protein phosphatase (PP2C), serves as a conserved CO2 sensor in fungi. By combining phosphoproteomic and biochemical assays, we identified Hsp90 as a direct target of Ptc2 at host CO2 concentrations and Ssb1 as a Ptc2 target protein regardless of CO2 levels in Candida albicans, the most prevalent human fungal pathogen. Ptc2 forms reversible condensates at elevated CO2, which enables the recruitment of Hsp90, but not Ssb1, to condensates, allowing efficient dephosphorylation. This process confers an enhanced susceptibility to caspofungin in vitro and during in vivo infection therapy. Importantly, we demonstrate this phenomenon in non-albicans Candida species. Sequential passages of C. albicans in mice with caspofungin treatment readily induce in vivo drug tolerance, causing therapeutic failure. These evolved strains display increased resistance to caspofungin under host concentrations of CO2 but remain susceptible in air. Collectively, our study reveals a profound impact of host concentrations of CO2 on antifungal drug susceptibility and connects this phenotype to therapeutic outcomes and highlights condensate formation as an efficient means that enables selective recruitment of substrates for certain signaling events.