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.

Download full-text


Available from: Karen Marchillo, Jan 15, 2014
15 Reads
  • Source
    • " 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 ) ."
    [Show abstract] [Hide abstract]
    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 · 9.47 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Candida albicans infections have become increasingly recognised as being biofilm related. Recent studies have shown that there is a relationship between biofilm formation and poor clinical outcomes in patients infected with biofilm proficient strains. Here we have investigated a panel of clinical isolates in an attempt to evaluate their phenotypic and transcriptional properties in an attempt to differentiate and define levels of biofilm formation. Results Biofilm formation was shown to be heterogeneous; with isolates being defined as either high or low biofilm formers (LBF and HBF) based on different biomass quantification. These categories could also be differentiated using a cell surface hydrophobicity assay with 24 h biofilms. HBF isolates were more resistance to amphotericin B (AMB) treatment than LBF, but not voriconazole (VRZ). In a Galleria mellonella model of infection HBF mortality was significantly increased in comparison to LBF. Histological analysis of the HBF showed hyphal elements intertwined indicative of the biofilm phenotype. Transcriptional analysis of 23 genes implicated in biofilm formation showed no significant differential expression profiles between LBF and HBF, except for Cdr1 at 4 and 24 h. Cluster analysis showed similar patterns of expression for different functional classes of genes, though correlation analysis of the 4 h biofilms with overall biomass at 24 h showed that 7 genes were correlated with high levels of biofilm, including Als3, Eap1, Cph1, Sap5, Plb1, Cdr1 and Zap1. Conclusions Our findings show that biofilm formation is variable amongst C. albicans isolates, and categorising isolates depending on this can be used to predict how pathogenic the isolate will behave clinically. We have shown that looking at individual genes in less informative than looking at multiple genes when trying to categorise isolates at LBF or HBF. These findings are important when developing biofilm-specific diagnostics as these could be used to predict how best to treat patients infected with C. albicans. Further studies are required to evaluate this clinically.
    BMC Microbiology 07/2014; 14(1):182. DOI:10.1186/1471-2180-14-182 · 2.73 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
Show more