Accumulation of trehalose 6-phosphate in Candidozyma auris results in decreased echinocandin resistance and tolerance

Candidozyma auris is an emerging multidrug-resistant fungal pathogen that poses a major public-health challenge owing to high mortality and the limited efficacy of current therapies. Echinocandins, which inhibit β-glucan synthesis, are first-line therapy for invasive C. auris infection; however, resistance to this class is rising, underscoring the urgent need for new antifungal targets. Here we show that enzymes in the trehalose-biosynthetic pathway regulate stress responses, antifungal resistance/tolerance and virulence in C. auris. The tps2Δ strain displays heightened susceptibility to echinocandins, whereas tps1Δ and tps1Δ tps2Δ strains show resistance and tolerance comparable to wild type (WT). Mechanistically, the tps2Δ strain accumulates trehalose 6-phosphate (T6P), which inhibits hexokinase activity and reduces the flux of glucose 6-phosphate (G6P) into the chitin biosynthesis pathway, leading to substantially decreased cell wall chitin. During echinocandin exposure, the tps2Δ strain fails to compensate for reduced β-glucan with increased chitin, thereby rendering it highly susceptible to these drugs. In a systemic mouse infection model, deletion of the TPS2 gene results in lower tissue fungal burdens after treatment with caspofungin. Together, these findings identify Tps2 as a potential therapeutic target that can potentiate echinocandin efficacy in C. auris via a distinct mechanism of action.