Role of Fks1p and matrix glucan on C. albicans biofilm resistance to an echinocandin, pyrimidine, and polyene
ABSTRACT 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.
Full-textDOI: · Available from: Karen Marchillo, Jan 15, 2014
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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 ) ."
ABSTRACT: Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.Cold Spring Harbor Perspectives in Medicine 11/2014; 5(7). DOI:10.1101/cshperspect.a019752 · 7.56 Impact Factor
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- "Firstly, the gene FKS1, encoding a b-1,3-glucan synthase which is the target for the echinocandin class of antifungals, was shown to be necessary for resistance, since viability of cells in a biofilm produced by a heterozygous deletion mutant which showed a 30 % reduction in b-1,3-glucans content, was reduced with 80 % after 48 h of treatment with 250 lg/ml fluconazole . A similar effect was not observed in planktonic cells (Nett et al. 2010). Furthermore, genes involved in the protein kinase C cell-wall integrity pathway, which controls cell-wall glucan content in response to stress, namely SMI1 and RLM1, were shown to be essential for C. albicans matrix and cell-wall b-1,3-glucan content (Nett et al. 2011). "
ABSTRACT: Like other microorganisms, free-living Candida albicans is mainly present in a three-dimensional multicellular structure, which is called a biofilm, rather than in a planktonic form. Candida albicans biofilms can be isolated from both abiotic and biotic surfaces at various locations within the host. As the number of abiotic implants, mainly bloodstream and urinary catheters, has been increasing, the number of biofilm-associated bloodstream or urogenital tract infections is also strongly increasing resulting in a raise in mortality. Cells within a biofilm structure show a reduced susceptibility to specific commonly used antifungals and, in addition, it has recently been shown that such cells are less sensitive to killing by components of our immune system. In this review, we summarize the most important insights in the mechanisms underlying biofilm-associated antifungal drug resistance and immune evasion strategies, focusing on the most recent advances in this area of research.Current Genetics 08/2013; 59(4). DOI:10.1007/s00294-013-0400-3 · 2.68 Impact Factor
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- "The role of extracellular matrix was investigated using strains previously described with altered expression of FKS1 (Nett et al., 2010a). Reference strain (DAY185), FKS1/fks1Δ and TDH3-FKS1 were standardized to 1 × 10 6 cells/ml in 96-well flat-bottomed plates and biofilms grown for 8 h at 37˚C. "
ABSTRACT: Carbohydrate derived fulvic acid (CHD-FA) is a heat stable low molecular weight, water soluble, cationic, colloidal material with proposed therapeutic properties. The aim of this study was to evaluate the antifungal activity of CHD-FA against Candida albicans, and to characterize its mode of action. A panel of C. albicans isolates (n = 50) derived from a range of clinical specimens were grown planktonically and as biofilms, and the minimum inhibitory concentrations determined. Scanning electron microscopy was performed to examine ultrastructural changes and different cell membrane assays were used to determine its mode of action. In addition, the role of C. albicans biofilm resistance mechanisms were investigated to determine their effects on CHD-FA activity. CHD-FA was active against planktonic and sessile C. albicans at concentrations 0.125 and 0.25% respectively, and was shown to be fungicidal, acting through disruption of the cell membrane activity. Resistance mechanisms, including matrix, efflux, and stress, had a limited role upon CHD-FA activity. Overall, based on the promising in vitro spectrum of activity and minimal biofilm resistance of the natural and cheap antiseptic CHD-FA, further studies are required to determine its applicability for clinical use.Frontiers in Microbiology 03/2012; 3:116. DOI:10.3389/fmicb.2012.00116 · 3.94 Impact Factor