Metabolic pathway competition sensitizes thioredoxin reductase-depleted <i>Candida albicans</i> to cell wall stress and antifungals

<i>Candida albicans</i> is the most common invasive human fungal pathogen. Each of the currently available 3 antifungal drug classes is limited by toxicities, drug interactions or inadequate penetration of critical tissues. We discovered a connection between <i>C. albicans</i> TOR and thioredoxin reductase, Trr1. Fungal and human thioredoxin reductases diverge fundamentally and are essential for repair of oxidatively damaged macromolecules, so they may be promising drug targets. We found that Trr1 is required for <i>C. albicans</i> ' growth at human body temperatures, hyphal growth regulation and management of oxidative and cell wall stress. Its depletion sensitizes <i>C. albicans</i> to AmphotericinB and to an echinocandin. <i>TRR1</i> -depleted cells have lower cell wall glucan content. Metabolomics experiments highlighted their perturbed pentose phosphate pathway (PPP). They have sharply elevated activity of glucose-6-phosphate dehydrogenase, the first, rate-limiting enzyme of the PPP. A key glycolytic, gluconeogenic and UDP-glucose biosynthetic enzyme each show decreased activity. UDP-glucose is the substrate of cell wall glucan-producing enzymes. We propose that Trr1-depleted cells' accelerated glucose-6-phosphate flux into the PPP, driven by demand for NADPH reducing equivalents, diminishes glucose-6-phosphate availability for UDP-glucose production and hence for cell wall construction, weakening the wall. Strikingly dysregulated signaling pathways in Trr1-depleted cells contribute to their stress hypersensitivities.