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Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans.

ABSTRACT: Candida albicans is known as a commensal microorganism but it is also the most common fungal pathogen in humans, causing both mucosal and systemic infections. Biofilm-associated C. albicans infections present clinically important features due to their high levels of resistance to traditional antifungal agents. Quorum sensing is closely associated with biofilm formation and increasing fungal pathogenicity. We investigated the ability of the novel bacterial quorum sensing quencher thiazolidinedione-8 (S-8) to inhibit the formation of, and eradication of mature C. albicans biofilms. In addition, the capability of S-8 to alter fungal adhesion to mammalian cells was checked. S-8 exhibited specific antibiofilm and antiadhesion activities against C. albicans, at four- to eightfold lower concentrations than the minimum inhibitory concentration (MIC). Using fluorescence microscopy, we observed that S-8 dose-dependently reduces C. albicans-GFP binding to RAW macrophages. S-8 at sub-MICs also interfered with fungal morphogenesis by inhibiting the yeast-to-hyphal form transition. In addition, the tested agent strongly affected fungal cell wall characteristics by modulating its hydrophobicity. We evaluated the molecular mode of S-8 antibiofilm and antiadhesion activities using real-time RT-PCR. The expression levels of genes associated with biofilm formation, adhesion and filamentation, HWP1, ALS3 and EAP1, respectively, were dose-dependently downregulated by S-8. Transcript levels of UME6, responsible for long-term hyphal maintenance, were also significantly decreased by the tested agent. Both signaling pathways of hyphal formation-cAMP-PKA and MAPK-were interrupted by S-8. Their upstream general regulator RAS1 was markedly suppressed by S-8. In addition, the expression levels of MAPK cascade components CST20, HST7 and CPH1 were downregulated by S-8. Finally, transcriptional repressors of filament formation, TUP1 and NRG1, were dramatically upregulated by our compound. Our results indicate that S-8 holds a novel antibiofilm therapeutic mean in the treatment and prevention of biofilm-associated C. albicans infections.

SUBMITTER: Feldman M

PROVIDER: S-EPMC4010395 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans.

Feldman Mark M Al-Quntar Abed A Polacheck Itzhak I Friedman Michael M Steinberg Doron D

PloS one 20140505 5

Candida albicans is known as a commensal microorganism but it is also the most common fungal pathogen in humans, causing both mucosal and systemic infections. Biofilm-associated C. albicans infections present clinically important features due to their high levels of resistance to traditional antifungal agents. Quorum sensing is closely associated with biofilm formation and increasing fungal pathogenicity. We investigated the ability of the novel bacterial quorum sensing quencher thiazolidinedion ...[more]

PMID: 24796422

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Project description:Substantial drug resistance afforded by Candida albicans biofilms results in ineffective treatment with conventional drugs and persistent infection. Our previous study showed that hexyl-aminolevulinate ethosomes (HAL-ES) act against C. albicans biofilms and weaken their drug resistance and pathogenicity; however, the mechanism involved remains unclear. Here, we systematically evaluated the effects and mechanisms of HAL-ES on biofilm formation and drug resistance. We found that, in addition to mediating antifungal photodynamic therapy, HAL-ES inhibited the early, developmental, and mature stages of biofilm formation compared with fluconazole, HAL, or ES. Notably, adhesion and hyphal formation were significantly inhibited by postdrug effects even after brief exposure (2 h) to HAL-ES. Its therapeutic effect in vivo also has been demonstrated in cutaneous candidiasis. RNA sequencing and quantitative PCR showed that HAL-ES inhibited ribosome biogenesis by disrupting zinc homeostasis in C. albicans, thereby reducing the translation process during protein synthesis. Furthermore, HAL-ES downregulated the expression of multidrug resistance genes and increased fluconazole susceptibility in C. albicans. Our findings provide a novel and efficient method for the treatment of biofilm resistance in C. albicans infection as well as a basis for the application of HAL-ES. We also describe a new strategy for the treatment of biofilm-related infections via zinc restriction. IMPORTANCE Candida albicans is the most prevalent fungal species of the human microbiota. The medical impact of C. albicans on its human host depends on its ability to form biofilms. The intrinsic resistance conferred by biofilms to conventional antifungal drugs makes biofilm-based infections a significant clinical challenge. In this study, we demonstrate the attenuating effect of HAL-ES on C. albicans biofilm formation and drug resistance. Furthermore, we propose that HAL-ES inhibits protein translation by disrupting zinc homeostasis in C. albicans. This study not only provides a novel and effective therapeutic strategy against C. albicans biofilm but also proposes a new strategy to resolve C. albicans biofilm infection by disrupting zinc homeostasis.

Dataset Information

Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans.

Publications

Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans.

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