title: Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis.
abstract: Infection by pathogenic fungi, such as Candida albicans, begins with adhesion to host cells or implanted medical devices followed by biofilm formation. By high-throughput phenotypic screening of small molecules, we identified compounds that inhibit adhesion of C. albicans to polystyrene. Our lead candidate compound also inhibits binding of C. albicans to cultured human epithelial cells, the yeast-to-hyphal morphological transition, induction of the hyphal-specific HWP1 promoter, biofilm formation on silicone elastomers, and pathogenesis in a nematode infection model as well as alters fungal morphology in a mouse mucosal infection assay. We term this compound filastatin based on its strong inhibition of filamentation, and we use chemical genetic experiments to show that it acts downstream of multiple signaling pathways. These studies show that high-throughput functional assays targeting fungal adhesion can provide chemical probes for study of multiple aspects of fungal pathogenesis.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Fazly
authors.forename: Charu
authors.initials: C
authors.lastname: Jain
authors.forename: Amie C
authors.initials: AC
authors.lastname: Dehner
authors.forename: Luca
authors.initials: L
authors.lastname: Issi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lilly
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fidel
authors.forename: Reeta P
authors.initials: RP
authors.lastname: Rao
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000187:drug effects* / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D025301:Hyphae / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D009348:Nematoda; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011137:Polystyrenes / Q000737:chemistry; D054852:Small Molecule Libraries / Q000032:analysis*
chemical_list: D010879:Piperazines; D011137:Polystyrenes; D054852:Small Molecule Libraries; C584247:filastatin
keywords: fungal pathogens; hyphal morphogenesis; small molecule screening
references.citation: PLoS Pathog. 2006 Jul;2(7):e63
references.pmid: 16839200
references.citation: PLoS One. 2011;6(9):e25395
references.pmid: 21966518
references.citation: Laryngoscope. 2002 Apr;112(4):708-12
references.pmid: 12152601
references.citation: Eukaryot Cell. 2004 Aug;3(4):919-31
references.pmid: 15302825
references.citation: Annu Rev Microbiol. 2002;56:139-65
references.pmid: 12142485
references.citation: Eukaryot Cell. 2009 Aug;8(8):1218-27
references.pmid: 19502579
references.citation: Cell. 2012 Jan 20;148(1-2):126-38
references.pmid: 22265407
references.citation: Trends Microbiol. 2004 Jul;12(7):317-24
references.pmid: 15223059
references.citation: Clin Microbiol Rev. 1996 Jul;9(3):335-48
references.pmid: 8809464
references.citation: Science. 2001 Feb 2;291(5505):878-81
references.pmid: 11157168
references.citation: J Antimicrob Chemother. 1999 Mar;43(3):411-3
references.pmid: 10223599
references.citation: Microbiology (Reading). 2010 Dec;156(Pt 12):3635-3644
references.pmid: 20705667
references.citation: PLoS One. 2009 Sep 14;4(9):e7025
references.pmid: 19750012
references.citation: Methods Mol Biol. 2009;499:197-201
references.pmid: 19152050
references.citation: Am J Obstet Gynecol. 1998 Feb;178(2):203-11
references.pmid: 9500475
references.citation: Genetics. 2001 Apr;157(4):1523-30
references.pmid: 11290709
references.citation: Mol Biol Cell. 2005 Jun;16(6):2903-12
references.pmid: 15814840
references.citation: Nat Rev Microbiol. 2011 Feb;9(2):109-18
references.pmid: 21189476
references.citation: J Bacteriol. 1999 Oct;181(20):6339-46
references.pmid: 10515923
references.citation: BMC Microbiol. 2011 Nov 04;11:247
references.pmid: 22053894
references.citation: Clin Infect Dis. 2001 Apr 1;32(7):1110
references.pmid: 11264044
references.citation: Nat Rev Drug Discov. 2011 Jun 24;10(7):507-19
references.pmid: 21701501
references.citation: Eukaryot Cell. 2003 Oct;2(5):1053-60
references.pmid: 14555488
references.citation: PLoS Genet. 2009 Dec;5(12):e1000783
references.pmid: 20041210
references.citation: Cell. 1997 Sep 5;90(5):939-49
references.pmid: 9298905
references.citation: PLoS Biol. 2011 Jul;9(7):e1001105
references.pmid: 21811397
references.citation: PLoS Pathog. 2008 Dec;4(12):e1000227
references.pmid: 19057660
references.citation: Cell Microbiol. 2006 Sep;8(9):1382-91
references.pmid: 16848788
references.citation: Antimicrob Agents Chemother. 2009 Sep;53(9):3963-71
references.pmid: 19596881
references.citation: Bioorg Med Chem Lett. 2011 Sep 15;21(18):5502-5
references.pmid: 21802942
references.citation: Mol Biol Cell. 2007 Mar;18(3):815-26
references.pmid: 17182857
references.citation: Virulence. 2013 Jan 1;4(1):67-76
references.pmid: 23314569
references.citation: Curr Opin Microbiol. 2011 Aug;14(4):380-5
references.pmid: 21741878
references.citation: Eukaryot Cell. 2011 Nov;10(11):1448-54
references.pmid: 21890817
references.citation: Clin Infect Dis. 2003 Sep 1;37(5):634-43
references.pmid: 12942393
references.citation: Mol Gen Genet. 1984;198(2):179-82
references.pmid: 6394964
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