title: Gymnemic acids inhibit hyphal growth and virulence in Candida albicans.
abstract: Candida albicans is an opportunistic and polymorphic fungal pathogen that causes mucosal, disseminated and invasive infections in humans. Transition from the yeast form to the hyphal form is one of the key virulence factors in C. albicans contributing to macrophage evasion, tissue invasion and biofilm formation. Nontoxic small molecules that inhibit C. albicans yeast-to-hypha conversion and hyphal growth could represent a valuable source for understanding pathogenic fungal morphogenesis, identifying drug targets and serving as templates for the development of novel antifungal agents. Here, we have identified the triterpenoid saponin family of gymnemic acids (GAs) as inhibitor of C. albicans morphogenesis. GAs were isolated and purified from Gymnema sylvestre leaves, the Ayurvedic traditional medicinal plant used to treat diabetes. Purified GAs had no effect on the growth and viability of C. albicans yeast cells but inhibited its yeast-to-hypha conversion under several hypha-inducing conditions, including the presence of serum. Moreover, GAs promoted the conversion of C. albicans hyphae into yeast cells under hypha inducing conditions. They also inhibited conidial germination and hyphal growth of Aspergillus sp. Finally, GAs inhibited the formation of invasive hyphae from C. albicans-infected Caenorhabditis elegans worms and rescued them from killing by C. albicans. Hence, GAs could be useful for various antifungal applications due to their traditional use in herbal medicine.
authors.affiliation: Division of Biology, Kansas State University, Manhattan, Kansas, United States of America ; Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France ; INRA, USC2019, Paris, France.
authors.forename: Govindsamy
authors.initials: G
authors.lastname: Vediyappan
authors.forename: Vincent
authors.initials: V
authors.lastname: Dumontet
authors.forename: Franck
authors.initials: F
authors.lastname: Pelissier
authors.forename: Christophe
authors.initials: C
authors.lastname: d'Enfert
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000382:microbiology; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D031104:Gymnema sylvestre / Q000737:chemistry*; D006801:Humans; D025301:Hyphae / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D010936:Plant Extracts / Q000737:chemistry; D012503:Saponins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013172:Spores, Fungal / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014774:Virulence / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D010936:Plant Extracts; D012503:Saponins; D014315:Triterpenes; C007898:gymnemic acid
references.citation: Mol Microbiol. 1999 Nov;34(4):651-62
references.pmid: 10564506
references.citation: Microbiol Mol Biol Rev. 2011 Jun;75(2):213-67
references.pmid: 21646428
references.citation: Chem Pharm Bull (Tokyo). 1992 Jun;40(6):1366-75
references.pmid: 1327559
references.citation: Mol Microbiol. 2008 Jan;67(1):47-62
references.pmid: 18078440
references.citation: Nature. 2001 Jun 14;411(6839):843-7
references.pmid: 11459067
references.citation: Sabouraudia. 1975 Jul;13(2):148-53
references.pmid: 808868
references.citation: Trends Microbiol. 2007 Apr;15(4):181-90
references.pmid: 17321137
references.citation: Science. 1999 Mar 5;283(5407):1535-8
references.pmid: 10066176
references.citation: Microbiol Mol Biol Rev. 2007 Jun;71(2):348-76
references.pmid: 17554048
references.citation: Crit Rev Microbiol. 2010;36(1):1-53
references.pmid: 20088682
references.citation: Crit Rev Microbiol. 2009;35(4):340-55
references.pmid: 19863383
references.citation: Planta Med. 1995 Feb;61(1):76-7
references.pmid: 7700999
references.citation: Infect Disord Drug Targets. 2008 Mar;8(1):2-15
references.pmid: 18473903
references.citation: J Altern Complement Med. 2007 Nov;13(9):977-83
references.pmid: 18047444
references.citation: Commun Integr Biol. 2011 Mar;4(2):240-2
references.pmid: 21655451
references.citation: PLoS One. 2012;7(9):e45912
references.pmid: 23049891
references.citation: Eukaryot Cell. 2013 Feb;12(2):224-32
references.pmid: 23223035
references.citation: Nat Rev Microbiol. 2011 Feb;9(2):109-18
references.pmid: 21189476
references.citation: J Pathol. 1969 Feb;97(2):357-66
references.pmid: 5352808
references.citation: Clin Microbiol Rev. 2007 Jan;20(1):133-63
references.pmid: 17223626
references.citation: FEMS Yeast Res. 2009 Feb;9(1):126-42
references.pmid: 19054126
references.citation: Microbiol Mol Biol Rev. 2003 Sep;67(3):400-28, table of contents
references.pmid: 12966142
references.citation: J Clin Biochem Nutr. 2007 Sep;41(2):77-81
references.pmid: 18193099
references.citation: J Bacteriol. 1982 Nov;152(2):555-62
references.pmid: 6752114
references.citation: Microbiology (Reading). 2004 Jul;150(Pt 7):2415-2428
references.pmid: 15256583
references.citation: Science. 1997 Jul 4;277(5322):105-9
references.pmid: 9204892
references.citation: Clin Infect Dis. 2009 Feb 1;48(3):265-73
references.pmid: 19115967
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):599-604
references.pmid: 19116272
references.citation: Curr Drug Targets. 2006 Apr;7(4):465-70
references.pmid: 16611034
references.citation: Crit Rev Microbiol. 1985;12(1):45-93
references.pmid: 3893894
references.citation: Cell. 1997 Sep 5;90(5):939-49
references.pmid: 9298905
references.citation: Genetics. 2000 May;155(1):57-67
references.pmid: 10790384
references.citation: Eukaryot Cell. 2011 Sep;10(9):1173-82
references.pmid: 21764907
references.citation: Annu Rev Microbiol. 2007;61:529-53
references.pmid: 17506678
references.citation: Infect Immun. 2009 Apr;77(4):1596-605
references.pmid: 19188358
references.citation: Infect Immun. 2006 Dec;74(12):6785-96
references.pmid: 16982843
references.citation: Eukaryot Cell. 2009 Nov;8(11):1750-8
references.pmid: 19666778
references.citation: PLoS Pathog. 2010 Oct 07;6(10):e1001140
references.pmid: 20949076
references.citation: Clin Infect Dis. 2009 Jun 15;48(12):1695-703
references.pmid: 19441981
references.citation: J Immunol. 1963 Sep;91:416-24
references.pmid: 14071033
references.citation: Pharmazie. 2003 Jan;58(1):5-12
references.pmid: 12622244
references.citation: Nat Protoc. 2008;3(12):1925-31
references.pmid: 19180076
references.citation: ACS Chem Biol. 2010 Mar 19;5(3):321-32
references.pmid: 20099897
references.citation: Mol Gen Genet. 1984;198(2):179-82
references.pmid: 6394964
references.citation: Curr Genet. 2003 Oct;44(1):1-7
references.pmid: 12819929
references.citation: J Bacteriol. 1999 Mar;181(6):1868-74
references.pmid: 10074081
references.citation: Eukaryot Cell. 2011 Aug;10(8):1034-42
references.pmid: 21666074
references.citation: PLoS Pathog. 2008 Dec;4(12):e1000244
references.pmid: 19096510
references.citation: PLoS Pathog. 2007 Jun;3(6):e92
references.pmid: 17604452
references.citation: Nat Genet. 2010 Jul;42(7):590-8
references.pmid: 20543849
references.citation: Eukaryot Cell. 2011 Aug;10(8):1004-12
references.pmid: 21642508
references.citation: Infect Immun. 2002 Nov;70(11):6319-29
references.pmid: 12379711