Role of Fks1p and Matrix Glucan in Candida albicans Biofilm Resistance to an Echinocandin, Pyrimidine, and Polyene

Department of Medicine, University of Wisconsin, 600 Highland Ave., H4/572 Clinical Sciences Center, Madison, WI 53792, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 08/2010; 54(8):3505-8. DOI: 10.1128/AAC.00227-10
Source: PubMed


Candida infections frequently involve drug-resistant biofilm growth on device surfaces. Glucan synthase gene FKS1 has been linked to triazole resistance in Candida biofilms. We tested the impact of FKS1 modulation on susceptibility to additional antifungal classes. Reduction of FKS1 expression rendered biofilms more susceptible to amphotericin B, anidulafungin, and flucytosine. Increased resistance to
anidulafungin and amphotericin B was observed for biofilms overexpressing FKS1. These findings suggest that Candida biofilm glucan sequestration is a multidrug resistance mechanism.

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Available from: Karen Marchillo, Jan 15, 2014
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    • "albicanscellswerehyper-susceptibletoCHD-FAinthepresence ofachitinsynthaseinhibitor,afindingthatwasalsoobservedin voriconazoletreatedbiofilms(Kanekoetal.,2010).Collectively, thesedatasuggestthatCHD-FAactsthroughdisruptiontothe cellmembrane.Itisthereforefeasibletosuggestthatthisagent mayhavebroad-spectrumantimicrobialactivityagainstavariety offungiandbacteria.Indeed,thiswasthecasewhenCHD-FA wasshowntopossessantibacterialactivitytowardarangeoforal bacterialbiofilms,includinganinvitrofour-speciesperiodontal biofilmmodel(Sherryetal.,2013). Additionally,fulvicacidwasshowntobeminimallyaffected bycharacterizedbiofilmresistancemechanisms,includingthe extracellularmatrix(ECM)andeffluxpumps.Forexample,it isknownthatglucanswithinthecellularmatrixhinderthe penetrationofazolesthroughbiofilms,withthedepletionofFKS1, encodingaβ-1,3glucansynthase,increasingthesusceptibility offluconazolewithinthesecommunities(Nettetal.,2010a,b). OverexpressionofFKS1,aswellasadeletionmutant,wasused todeterminetheimpactofCHD-FAactivity.Hereitwasshown thatthisagent'ssensitivitywasnotcompromisedbytheelevated expressionofFKS1,whichisincontrasttoazoles,polyenesand echinocandins,wherethematrixsequesterstheseagentsandtheir activityissignificantlyreducedagainstC.albicansbiofilms(Nett "
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    • " glabrata , C . parapsilosis , C . tropicalis , and C . dubliniensis ( Silva et al . 2009 ) . A key biofilm constituent is b - 1 , 3 - glucan , which is produced by glucan syn - thase . Downstream components of the yeast PKC pathway , including Smi1 , Rlm1 , Rho1 , and Fsk1 , regulate b - 1 , 3 - glucan biosynthesis and biofilm matrix production ( Nett et al . 2010a , b , 2011 ; Desai et al . 2013 ) . Other cellular proteins , such as the transcription factor Zap1 , alcohol dehydrogenases Adh5 , Csh1 , and Ifd6 , as well as glucoamylases , CaGca1 and CaGca2 , also affect matrix production and resistance pheno - types ( Nobile et al . 2009 ) ."
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    • "We examined azole treatment, which unsurprisingly demonstrated poor activity overall with no group differences, presumably through adaptive resistance mechanisms as previously described [22-24]. Notably, AMB was less effective against HBF biofilms than LBF, which we hypothesise is due to the inability of the compound to permeate easily throughout the dense physical structure of the cells encased within ECM [25]. We purposely excluded echinocandins from this study as these have been shown to be an effective anti-biofilm antifungals, therefore quantifying differences in activity against the two populations would be difficult [26]. "
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