Streptomyces induces unisexual reproduction of a major human fungal pathogen

Cryptococcus, a human pathogenic yeast, can undergo unisexual reproduction in the absence of compatible mating partners, yet this developmental program remains poorly understood. Here, we report that tunicamycin, a natural product produced by Streptomyces species, induces a complete unisexual reproductive cycle in different Cryptococcus species. Bacterial confrontation or purified tunicamycin trigger hyphal differentiation, meiotic recombination, and basidiospore formation, as confirmed by whole-genome sequencing and SNP analyses. We further demonstrate that tunicamycin-induced unisexual development requires canonical sexual regulators and meiotic machinery. Transcriptomic profiling reveals staged developmental reprogramming characterized by early induction of stress- and cell cycle-associated genes, followed by enrichment of genes in the filamentation-related pathways. This capacity varies among natural isolates of C. neoformans and was conserved in Cryptococcus gattii. Together, our findings demonstrate that a bacterial metabolite can activate meiotically competent unisexual reproduction, highlighting interkingdom chemical signaling as a potential driver of fungal evolution in natural environments.