AUTHOR=Wu Jiadi , Wu Daqiang , Zhao Yeye , Si Yuanqing , Mei Longfei , Shao Jing , Wang Tianming , Yan Guiming , Wang Changzhong 

TITLE=Sodium New Houttuyfonate Inhibits Candida albicans Biofilm Formation by Inhibiting the Ras1-cAMP-Efg1 Pathway Revealed by RNA-seq

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.02075

DOI=10.3389/fmicb.2020.02075

ISSN=1664-302X

ABSTRACT=<p>Here, we aim to investigate the antifungal effect and mechanism of action of sodium new houttuyfonate (SNH) against <italic>Candida albicans</italic>. Microdilution analysis results showed that SNH possesses potent inhibitory activity against <italic>C. albicans</italic> SC5314, with a MIC<sub>80</sub> of 256 μg/mL. Furthermore, we found that SNH can effectively inhibit the initial adhesion of <italic>C. albicans</italic>. Inverted microscopy, crystal violet staining, scanning electron microscopy and confocal laser scanning microscopy results showed that morphological changes during the transition from yeast to hypha and the biofilm formation of <italic>C. albicans</italic> are repressed by SNH treatment. We also found that SNH can effectively inhibit the biofilm formation of clinical <italic>C. albicans</italic> strains (Z103, Z3044, Z1402, and Z1407) and SNH in combination with fluconazole, berberine chloride, caspofungin and itraconazole antifungal agents can synergistically inhibit the biofilm formation of <italic>C. albicans</italic>. Eukaryotic transcriptome sequencing and qRT-PCR results showed that SNH treatment resulted in significantly down-regulated expression in several biofilm formation related genes in the Ras1-cAMP-Efg1 pathway (<italic>ALS1, ALA1, ALS3, EAP1, RAS1, EFG1, HWP1</italic>, and <italic>TEC1</italic>) and significantly up-regulated expression in yeast form-associated genes (<italic>YWP1</italic> and <italic>RHD1</italic>). We also found that SNH can effectively reduce the production of key messenger cAMP in the Ras1-cAMP-Efg1 pathway. Furthermore, using <italic>Galleria mellonella</italic> as an <italic>in vivo</italic> model we found that SNH can effectively treat <italic>C. albican</italic>s infection <italic>in vivo</italic>. Our presented results suggest that SNH exhibits potential antibiofilm effects related to inhibiting the Ras1-cAMP-Efg1 pathway in the biofilm formation of <italic>C. albicans</italic>.</p>