Physiological and transcriptional profiling of surfactin exerted antifungal effect against Candida albicans
Authors: Jakab Ágnes , Kovács Fruzsina , Balla Noémi , Tóth Zoltán , Ragyák Ágota , Sajtos Zsófi , Csillag Kinga , Nagy-Köteles Csaba , Nemes Dániel , Pócsi István , Majoros László , Kovács Ákos T. , Kovács Renátó 
Published: May 2022

AbstractGiven the risk of Candida albicans overgrowth in the gut, novel complementary therapies should be developed to reduce fungal dominancy. This study highlights the antifungal characteristics of a Bacillus subtilis-derived secondary metabolite, surfactin with high potential against C. albicans. Surfactin inhibited the growth of C. albicans following a 1-hour exposure, in addition to reduced adhesion and morphogenesis. Specifically, surfactin did not affect the level of reactive oxygen species but increased the level of reduced glutathione. Surprisingly, ethanol production enhanced following 2 hours of surfactin exposure. Surfactin treatment caused a significant reduction in intracellular iron, manganese and zinc content compared to control cells, whereas the level of copper was not affected. Alongside these physiological properties, surfactin also enhanced fluconazole efficacy. To gain detailed insights into the surfactin-related effects on C. albicans, genome-wide gene transcription analysis was performed. Surfactin treatment resulted in 1390 differentially expressed genes according to total transcriptome sequencing (RNA-Seq). Of these, 773 and 617 genes with at least a 1.5-fold increase or decrease in transcription, respectively, were selected for detailed investigation. Several genes involved in morphogenesis or related to metabolism (e.g., glycolysis, fermentation, fatty acid biosynthesis) were down-regulated. Moreover, surfactin decreased the expression of ERG1, ERG3, ERG9, ERG10 and ERG11 involved in ergosterol synthesis, whereas genes associated with ribosome biogenesis and iron metabolism and drug transport-related genes were up-regulated. Our data demonstrate that surfactin significantly influences the physiology and gene transcription of C. albicans, and could contribute to the development of a novel innovative complementary therapy.ImportanceAlthough gut colonization by Candida albicans can be considered normal, it may be associated with intestinal diseases. Furthermore, Candida dominance in the gut may pose a potent risk for systemic candidiasis, especially for immunocompromised individuals. In recent years, interest has been growing for the use of Bacillus subtilis as a safe and effective probiotic for human healthcare. Surfactin is a B. subtilis-derived lipopeptide with potential antifungal activity; however, the mechanism underlying this remains unknown. In this study, surfactin negatively affected the adherence, morphogenesis and metabolism of C. albicans and increased ethanol production. These were associated with a reduction in intracellular iron, manganese and zinc while the copper content was not affected. Alongside these physiological modulations, surfactin also had a potent synergistic effect on fluconazole. Our results provide a definitive explanation for the surfactin-related antifungal effect of B. subtilis; furthermore, these data provide a good basis for future probiotic development.