Cascading damage to <i>Candida albicans</i> cells through thioredoxin reductase loss.

Abstract

<i>Candida albicans</i> is the most common invasive human fungal pathogen. We show that <i>C. albicans</i> thioredoxin reductase, Trr1, is an attractive antifungal target: it is essential at human body temperature, and fungal and human thioredoxin reductases are structurally divergent, predicting high selectivity of fungal-targeted inhibitors. <i>TRR1</i> depletion directly impairs oxidative damage repair, but also triggers cascading disruption of stress signaling and metabolic adaptation. Impaired oxidative stress endurance and consequent amphotericin hypersensitivity are anticipated effects of <i>TRR1</i> depletion. We unexpectedly find it also sensitizes <i>Candida</i> to cell wall stress and to a first-line echinocandin antifungal agent. <i>TRR1</i>-depleted cells have decreased cell wall glucan content. Driven by demand for NADPH reducing equivalents, these cells increase glucose-6-phosphate flux into the pentose phosphate pathway (PPP) as evinced by sharply elevated activity of the PPP's first, rate-limiting enzyme. Since UDP-glucose-the substrate for cell wall glucan biosynthesis-is also derived from glucose-6-phosphate, we propose that metabolic pathway competition for this shared intermediate between NADPH production and cell wall glucan biosynthesis underlies the cell wall weakness of <i>TRR1</i>-depleted cells. Decreased activity of a key UDP-glucose biosynthetic enzyme supports this mechanism. Trr1 loss of function further drives feed-forward damage cycles: it accelerates respiration which increases reactive oxygen species, reduces gluconeogenesis which further limits glucose-6-phosphate availability, and suppresses oxidative- and cell wall stress signaling pathways. Our findings support Trr1 inhibition as a promising approach to improved treatment of <i>C. albicans</i> infections.