Distinct polyamine effects on Candida albicans morphogenesis identify spermidine as a key regulator

Polyamines play essential and multifaceted roles in all organisms. However, their unique functions in fungal cell differentiation provide an opportunity to identify novel antifungal targets, as inhibition of essential metabolic pathways represents a promising therapeutic strategy. In this study, we characterized two putative regulators of the polyamine biosynthesis pathway in the major human fungal pathogen Candida albicans, identified based on their homology to Saccharomyces cerevisiae SPE1 and SPE2, which encode ornithine decarboxylase and S-adenosylmethionine decarboxylase, respectively. We generated single and double gene deletion strains for CaSPE1 and CaSPE2 and found that disruption of these genes severely impaired yeast cell growth due to disturbed polyamine homeostasis. This dysregulation was associated with pronounced cell vacuolar enlargement, indicating that cellular stress is linked to polyamine imbalance. Filamentation analyses revealed that polyamine-induced morphogenesis by spermine and spermidine is growth medium-dependent, likely reflecting differences in the bioavailability of different types of polyamines. Among the polyamines tested, spermine acted synergistically with glucose to promote filamentation in minimal medium. Collectively, our findings demonstrate that polyamines mediate a finely tuned balance between yeast cell proliferation and filamentous growth in C. albicans. Notably, spermidine directly regulates polyamine homeostasis to govern cell growth and filamentation, and spermine appears to be the primary polyamine driving filamentation, potentially through a dual signaling mechanism that integrates metabolic status and morphogenetic regulation.

Metabolic plasticity is a critical determinant of microbial commensalism and pathogenicity, shaped by the evolutionary pressure that drives niche-specific adaptations. These processes are not well understood in a species-specific context across diverse morphogenetic programs that govern fungal adaptations. As a major dimorphic human fungal pathogen, Candida albicans finely tunes its metabolic pathways to support its growth and virulence properties, including morphogenesis. Here, we investigated one such understudied pathway: polyamine metabolism under distinct growth conditions. Building upon previous studies on fungal polyamine biology, we demonstrated that polyamine homeostasis influences growth, cell morphology, and filamentation in C. albicans. This study expands our understanding of how diverse polyamines shape C. albicans physiology by providing insight into the dual roles of polyamines as nutrients and signaling molecules. These findings illustrate the complex relationship between polyamine metabolism and morphogenesis in C. albicans while identifying polyamine metabolism as a pathway of continued interest for antifungal target discovery.