A bacterial metabolite rewires fungal metabolism, triggering the hyphae-to-yeast transition.

Fungi transition between cell morphologies to adapt to and colonize environments. For Candida albicans, commensal colonization of humans and virulence depend on a reversible switch between invasive hyphae and disseminating yeast cells. The yeast-to-hyphae transition is well understood, but comparatively little is known about the reverse transition from hyphae back to yeast. By developing an imaging assay to visualize and quantify the hyphae-to-yeast transition, we show that the bacterial natural product gladiolin accelerates the transition. Gladiolin reprograms C. albicans metabolism, causing faster glucose consumption and increased cellular ergosterol content. In turn, faster glucose depletion accelerates the hyphae-to-yeast transition by decreasing glucose metabolism and signaling via Ras-cyclic AMP (cAMP). Transcriptional activators of glycolysis, Tye7 and Gal4, regulate the timing of the hyphae-to-yeast transition and contribute to its acceleration by gladiolin, while the ergosterol biosynthesis activator Upc2 represses the transition by maintaining hyphal elongation. Our findings shed light on the metabolic and regulatory programs that control the hyphae-to-yeast transition, revealing how changing nutrient levels and bacterial metabolites create conditions that may promote fungal dissemination.