title: Retigeric acid B attenuates the virulence of Candida albicans via inhibiting adenylyl cyclase activity targeted by enhanced farnesol production.
abstract: Candida albicans, the most prevalent fungal pathogen, undergoes yeast-to-hyphal switch which has long been identified as a key fungal virulence factor. We showed here that the lichen-derived small molecule retigeric acid B (RAB) acted as an inhibitor that significantly inhibited the filamentation of C. albicans, leading to the prolonged survival of nematodes infected by C. albicans. Quantitative real-time PCR analysis and intracellular cAMP measurement revealed RAB regulated the Ras1-cAMP-Efg1 pathway by reducing cAMP level to inhibit the hyphae formation. Confocal microscopic observation showed RAB induced the expression of Dpp3, synthesizing more farnesol, which was confirmed by gas chromatography-mass spectroscopy detection. An adenylyl cyclase activity assay demonstrated RAB could repress the activity of Cdc35 through stimulating farnesol synthesis, thus causing a decrease in cAMP synthesis, leading to retarded yeast-to-hyphal transition. Moreover, reduced levels of intracellular cAMP resulted in the inhibition of downstream adhesins. Together, these findings indicate that RAB stimulates farnesol production that directly inhibits the Cdc35 activity, reducing the synthesis of cAMP and thereby causing the disruption of the morphologic transition and attenuating the virulence of C. albicans. Our work illustrates the underlying mechanism of RAB-dependent inhibition of the yeast-to-hyphal switch and provides a potential application in treating the infection of C. albicans.
authors: School of Pharmaceutical Sciences, Shandong University, Jinan City, Shandong Province, China.
authors: Wenqiang
authors: W
authors: Chang
authors: Ying
authors: Y
authors: Li
authors: Li
authors: L
authors: Zhang
authors: Aixia
authors: A
authors: Cheng
authors: Hongxiang
authors: H
authors: Lou
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000382:microbiology; D002176:Candida albicans / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity*; D000242:Cyclic AMP / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005204:Farnesol / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D025301:Hyphae / Q000187:drug effects / Q000254:growth & development; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000935:Antifungal Agents; D004268:DNA-Binding Proteins; C121438:EFG1 protein, Candida albicans; D005656:Fungal Proteins; D014157:Transcription Factors; D014315:Triterpenes; C540615:retigeric acid B; D005204:Farnesol; D000242:Cyclic AMP; D018631:ras Proteins; D000262:Adenylyl Cyclases