title: Inhibition of electron transport chain assembly and function promotes photodynamic killing of Candida.
abstract: Respiratory deficiency increases the sensitivity of the pathogenic fungi Candida albicans and Candida glabrata to oxidative stress induced by photodynamic therapy (PDT) sensitized by the cationic porphyrin meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP-1363). Since disruption of electron transport chain (ETC) function increases intracellular levels of reactive oxygen species in yeast, we determined whether interference with ETC assembly or function increased sensitivity to TMP-1363-PDT in C. albicans, C. glabrata and the non-pathogenic yeast Saccharomyces cerevisiae. Metabolic inhibitor antimycin A and defined genetic mutants were used to identify ETC components that contribute to the sensitivity to PDT. Inhibition of cytochrome bc(1) (Complex III) with antimycin A increases mitochondrial levels of reactive oxygen species. PDT performed following pre-treatment with antimycin A reduced colony forming units (CFU) of C. albicans and C. glabrata by approximately two orders of magnitude relative to PDT alone. A S. cerevisiae mitochondrial glutaredoxin grx5 mutant, defective in assembly of Fe-S clusters critical for Complex III function, displayed increased sensitivity to PDT. Furthermore, C. glabrata and S.cerevisiae mutants in cytochrome c oxidase (Complex IV) synthesis and assembly were also significantly more sensitive to PDT. These included suv3, encoding an ATP-dependent RNA helicase critical for maturation of cytochrome c oxidase subunit transcripts, and pet117, encoding an essential cytochrome c oxidase assembly factor. Following PDT, the reduction in CFU of these mutants was one to two orders of magnitude greater than in their respective parental strains. The data demonstrate that selective inhibition of ETC Complexes III and IV significantly increases the sensitivity of C. albicans, C. glabrata and S. cerevisiae to PDT sensitized with TMP-1363.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Box 672, 601 Elmwood Ave., Rochester, NY 14642, USA.
authors.forename: Yeissa
authors.initials: Y
authors.lastname: Chabrier-Roselló
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Giesselman
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: De Jesús-Andino
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Foster
authors.forename: Soumya
authors.initials: S
authors.lastname: Mitra
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Haidaris
mesh_terms: D000968:Antimycin A / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000528:radiation effects*; D041221:Candida glabrata / Q000187:drug effects / Q000528:radiation effects*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000633:toxicity; D011166:Porphyrins / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; C057459:tetra(3-N-methylpyridyl)porphine; D000968:Antimycin A; D003576:Electron Transport Complex IV; C075918:SUV3 protein, S cerevisiae; D053487:DEAD-box RNA Helicases; D014450:Electron Transport Complex III
references.citation: J Antimicrob Chemother. 1998 Jul;42(1):13-28
references.pmid: 9700525
references.citation: FEMS Yeast Res. 2006 Nov;6(7):979-86
references.pmid: 17042747
references.citation: Clin Microbiol Rev. 1999 Jan;12(1):80-96
references.pmid: 9880475
references.citation: Mol Biol Cell. 2002 Apr;13(4):1109-21
references.pmid: 11950925
references.citation: Free Radic Biol Med. 2003 Feb 15;34(4):478-88
references.pmid: 12566073
references.citation: Antimicrob Agents Chemother. 2007 May;51(5):1855-8
references.pmid: 17325226
references.citation: J Biol Chem. 2004 Mar 26;279(13):12386-95
references.pmid: 14722110
references.citation: Photochem Photobiol. 2006 Sep-Oct;82(5):1178-86
references.pmid: 16740059
references.citation: Antimicrob Agents Chemother. 2001 Apr;45(4):1174-83
references.pmid: 11257032
references.citation: EMBO J. 2006 Apr 19;25(8):1775-83
references.pmid: 16601688
references.citation: Arch Biochem Biophys. 1985 Mar;237(2):408-14
references.pmid: 2983613
references.citation: J Mol Biol. 2007 Sep 7;372(1):23-36
references.pmid: 17658549
references.citation: Cell. 1996 Jan 26;84(2):199-209
references.pmid: 8565066
references.citation: Antimicrob Agents Chemother. 2004 May;48(5):1600-13
references.pmid: 15105111
references.citation: Free Radic Biol Med. 2003 Jul 15;35(2):179-88
references.pmid: 12853074
references.citation: J Biol Chem. 2003 Jan 17;278(3):1603-11
references.pmid: 12426313
references.citation: Mol Microbiol. 2006 Aug;61(3):704-22
references.pmid: 16803598
references.citation: Antimicrob Agents Chemother. 2005 Oct;49(10):4288-95
references.pmid: 16189110
references.citation: Mol Biol Cell. 2002 Mar;13(3):847-53
references.pmid: 11907266
references.citation: Mol Biol Cell. 2004 Jun;15(6):2674-83
references.pmid: 15047869
references.citation: J Photochem Photobiol B. 2009 Sep 4;96(3):223-31
references.pmid: 19651522
references.citation: J Antimicrob Chemother. 1995 Jan;35(1):103-14
references.pmid: 7768758
references.citation: Mol Cell Biol. 1999 Dec;19(12):8180-90
references.pmid: 10567543
references.citation: J Biol Chem. 2001 Feb 9;276(6):4020-7
references.pmid: 11054416
references.citation: Biochem Biophys Res Commun. 1968 Feb 15;30(3):232-9
references.pmid: 5647224
references.citation: Cell Microbiol. 2007 Feb;9(2):492-501
references.pmid: 16987332
references.citation: Arch Microbiol. 1978 Jan 23;116(1):61-7
references.pmid: 203238
references.citation: Biochim Biophys Acta. 2002 Oct 3;1556(1):73-80
references.pmid: 12351220
references.citation: Clin Microbiol Rev. 2004 Apr;17(2):255-67
references.pmid: 15084500
references.citation: J Bioenerg Biomembr. 2006 Apr;38(2):129-35
references.pmid: 17053999
references.citation: Exp Physiol. 2006 Sep;91(5):807-19
references.pmid: 16857720
references.citation: Antimicrob Agents Chemother. 2003 Mar;47(3):847-53
references.pmid: 12604511
references.citation: FEBS Lett. 1997 Jun 30;410(2-3):219-22
references.pmid: 9237633
references.citation: Curr Genet. 1993 Jan;23(1):9-14
references.pmid: 8381337
references.citation: Science. 1999 Aug 6;285(5429):901-6
references.pmid: 10436161
references.citation: Mycoses. 2006 Nov;49(6):445-51
references.pmid: 17022759
references.citation: J Photochem Photobiol B. 1999 Mar;49(1):18-22
references.pmid: 10365443
references.citation: J Dent Res. 2007 Mar;86(3):204-15
references.pmid: 17314251
references.citation: J Physiol. 2003 Oct 15;552(Pt 2):335-44
references.pmid: 14561818
references.citation: Photochem Photobiol Sci. 2004 May;3(5):403-5
references.pmid: 15122355
references.citation: Photochem Photobiol. 2008 Sep-Oct;84(5):1141-8
references.pmid: 18248505
references.citation: Methods Enzymol. 2001;342:367-78
references.pmid: 11586909
references.citation: Biochim Biophys Acta. 2008 Feb;1777(2):211-9
references.pmid: 18022381
references.citation: Biochim Biophys Acta. 2008 Nov;1780(11):1217-35
references.pmid: 18178164
references.citation: Diagn Microbiol Infect Dis. 1999 Apr;33(4):217-22
references.pmid: 10212747
references.citation: Antimicrob Agents Chemother. 2000 Feb;44(2):348-54
references.pmid: 10639361
references.citation: FEBS Lett. 2003 Jan 16;534(1-3):39-48
references.pmid: 12527359