Synergistic activity of caspofungin and posaconazole against Candida auris biofilms based on phenotypic, transcriptomic and in vivo insights

ABSTRACT: The World Health Organization (WHO) had designated Candida auris as a critical public health threat due to its multidrug resistance to antifungal agents, high mortality rate, and its ability to cause nosocomial outbreaks. A matter of serious concern is that conventional antifungal monotherapies is frequently ineffective against biofilm-associated C. auris infection, highlighting the need for more effective strategies. Combination therapies have demonstrated improved efficacy and specificity, and may also slow the development of antifungal resistance. Therefore, this study aimed to evaluate the in vitro and in vivo efficacy of caspofungin (CAS) and posaconazole (POSA) in combination against sessile C. auris isolates from the South Asian clade and to characterize the associated transcriptomic responses. The CAS with POSA combination resulted in a significant reduction in median minimum inhibitory concentrations (4–32-fold for CAS and 8–64-fold for POSA) compared to monotherapies. Synergistic interactions were observed in all isolates tested, with fractional inhibitory concentration indices ranging from 0.078 to 0.31. In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were three log volumes in mice treated with combination of 1 mg/kg/day caspofungin and 1.5 mg/kg/day posaconazole. To investigate the gene expression changes in response to combination treatment, 612 genes showed increased expression and 465 genes were downregulated relative to the untreated control biofilms (fold change >1.5 or <–1.5). Notably, genes involved in biofilm dispersion, oxidative stress response, iron metabolism, and glycolysis were downregulated, whereas those associated with cell wall organization or biogenesis, osmotic stress response, calcium signaling, drug efflux, biofilm formation, and the biosynthesis of ergosterol and chitin were upregulated. These findings demonstrate the potent synergistic activity of CAS and POSA against C. auris biofilms and provide insight into C. auris antifungal therapeutic responses, thereby contributing to the development of more effective antifungal treatment strategies.

ORGANISM(S): Candidozyma auris

PROVIDER: GSE302377 | GEO | 2025/09/01

REPOSITORIES: GEO