title: Biatriosporin D displays anti-virulence activity through decreasing the intracellular cAMP levels.
abstract: Candidiasis has long been a serious human health problem, and novel antifungal approaches are greatly needed. During both superficial and systemic infection, C. albicans relies on a battery of virulence factors, such as adherence, filamentation, and biofilm formation. In this study, we found that a small phenolic compound, Biatriosporin D (BD), isolated from an endolichenic fungus, Biatriospora sp., displayed anti-virulence activity by inhibiting adhesion, hyphal morphogenesis and biofilm formation of C. albicans. Of note is the high efficacy of BD in preventing filamentation with a much lower dose than its MIC value. Furthermore, BD prolonged the survival of worms infected by C. albicans in vivo. Quantitative real-time PCR analysis, exogenous cAMP rescue experiments and intracellular cAMP measurements revealed that BD regulates the Ras1-cAMP-Efg1 pathway by reducing cAMP levels to inhibit the hyphal formation. Further investigation showed that BD could upregulate Dpp3 to synthesize much more farnesol, which could inhibit the activity of Cdc35 and reduce the generation of cAMP. Taken together, these findings indicate that BD stimulates the expression of Dpp3 to synthesize more farnesol that directly inhibits the Cdc35 activity, reducing intracellular cAMP and thereby disrupting the morphologic transition and attenuating the virulence of C. albicans. Our study uncovers the underlying mechanism of BD as a prodrug in fighting against pathogenic C. albicans and provides a potential application of BD in fighting clinically relevant fungal infections by targeting fungal virulence.
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Hongzhuo
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China. Electronic address: louhongxiang@sdu.edu.cn.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D000072283:A549 Cells; D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005656:Fungal Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D014774:Virulence / Q000187:drug effects / Q000502:physiology*; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D001688:Biological Products; D005656:Fungal Proteins; D037521:Virulence Factors; D000242:Cyclic AMP
keywords: Anti-virulence; Biatriosporin D; Candida albicans; Farnesol; cAMP