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.
Highlights
The yeast Candida albicans is found as a commensal microorganism in the digestive tract of mammals [1], as well as in the oral cavity of humans [2]
Our results indicate that sensing quencher thiazolidinedione-8 (S-8) holds a novel antibiofilm therapeutic mean in the treatment and prevention of biofilm-associated C. albicans infections
Biofilm formation is an important factor in C. albicans pathogenesis [11]; it involves attachment, colonization and the development of a mature biofilm structure composed of yeast, pseudo- and true hyphae, and extracellular matrix [11,12,13,14]
Summary
The yeast Candida albicans is found as a commensal microorganism in the digestive tract of mammals [1], as well as in the oral cavity of humans [2] It is the most common fungal pathogen in humans, causing both mucosal and systemic infections, in immunocompromised individuals [3]. In contrast to the planktonic form, fungal biofilm is highly resistant to antifungal drugs This resistance is multifactorial and complex, involving: (i) limited drug penetration into the biofilm due to the high density of extracellular matrix, (ii) drug absorption or binding by the biofilm extracellular matrix, (iii) decreased growth rate, (iv) overexpression of genes involved in drug resistance, those encoding efflux pumps, (v) and multidrug tolerance due to persistant cells [11,13,15,16]The outcome of immobilized fungi in biofilm in terms of pathogenicity and drug resistance emphasizes the need for new antibiofilm agents that can inhibit biofilm formation or destroy preformed biofilm without affecting fungal viability
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