Acetylsalicylic acid (aspirin) reduces damage to reconstituted human tissues infected with Candida species by inhibiting extracellular fungal lipases.
A reconstituted human tissue model was used to mimic Candida albicans and Candida parapsilosis infection in order to investigate the protective effects of acetylsalicylic acid (aspirin, ASA). We found that therapeutic concentrations of ASA reduced tissue damage in the in vitro infection model. We further evaluated the lipase inhibitory effects of ASA by investigating the growth of C. albicans, C. parapsilosis and C. parapsilosis lipase negative (Deltacplip1-2/Deltacplip1-2) mutants in a lipid rich minimal medium supplemented with olive oil and found that a therapeutic concentration of ASA inhibited the growth of wild type fungi. The lipase inhibitors quinine and ebelactone B were also shown to reduce growth and protect against tissue damage from Candida species, respectively. A lipolytic activity assay also showed that therapeutic concentrations of ASA inhibited C. antarctica and C. cylindracea purified lipases obtained through a commercial kit. The relationship between ASA and lipase was characterized through a computed structural model of the Lipase-2 protein from C. parapsilosis in complex with ASA. The results suggest that development of inhibitors of fungal lipases could result in broad-spectrum therapeutics, especially since fungal lipases are not homologous to their human analogues.
Trofa
David
D
Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, NY 10461, USA.
Agovino
Mariangela
M
Stehr
Frank
F
Schäfer
Wilhelm
W
Rykunov
Dmitry
D
Fiser
András
A
Hamari
Zsuzsanna
Z
Nosanchuk
Joshua D
JD
Gácser
Attila
A
D001241:Aspirin / Q000494:pharmacology*; D002175:Candida / Q000145:classification / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D002177:Candidiasis / Q000382:microbiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004848:Epithelium / Q000254:growth & development / Q000382:microbiology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors*; D009055:Mouth / Q000166:cytology*
D005656:Fungal Proteins; D008049:Lipase; D001241:Aspirin
Jpn J Infect Dis. 2006 Apr;59(2):73-6
16632905
J Antibiot (Tokyo). 1987 Aug;40(8):1081-5
3680018
Mol Microbiol. 1999 Oct;34(1):169-80
10540295
J Biol Chem. 1994 May 6;269(18):13207-15
8175750
J Chemother. 2004 Apr;16(2):134-8
15216946
Biochemistry. 1995 Dec 26;34(51):16838-51
8527460
Nucleic Acids Res. 1999 Jan 1;27(1):12-7
9847132
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D247-51
16381856
Mycoses. 2005 Nov;48(6):365-77
16262871
Microbiology (Reading). 2001 Aug;147(Pt 8):1997-2005
11495978
Mol Gen Genet. 1984;198(2):179-82
6394964
FEMS Microbiol Lett. 2005 Apr 1;245(1):117-21
15796988
Clin Microbiol Rev. 2008 Oct;21(4):606-25
18854483
Fungal Genet Biol. 2007 Dec;44(12):1336-41
17391997
Antimicrob Agents Chemother. 2004 Jan;48(1):41-7
14693516
Int J Clin Pharmacol Ther Toxicol. 1981 Mar;19(3):112-6
7228453
Antonie Van Leeuwenhoek. 2007 May;91(4):393-405
17094014
Angew Chem Int Ed Engl. 1998 Jul 3;37(12):1608-1633
29711530
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Proc Natl Acad Sci U S A. 1975 Aug;72(8):3073-6
810797
J Infect. 1998 May;36(3):259-67
9661934
FEMS Yeast Res. 2004 Jan;4(4-5):401-8
14734020
Atherosclerosis. 1992 Apr;93(3):179-88
1534226
Nat New Biol. 1971 Jun 23;231(25):232-5
5284360
J Clin Invest. 2007 Oct;117(10):3049-58
17853941
Infect Immun. 2007 Oct;75(10):4710-8
17646357
J Biol Chem. 1993 Mar 25;268(9):6610-4
8454631
FEMS Microbiol Lett. 2001 Apr 20;198(1):37-43
11325551
J Invest Dermatol. 1978 Dec;71(6):398-401
722119
FEMS Microbiol Rev. 1994 Sep;15(1):29-63
7946464