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.

Sustained Release of a Novel Anti-Quorum-Sensing Agent against Oral Fungal Biofilms

“…This observation is of clinical importance, as C. albicans is a dimorphic fungal pathogen that is capable of reversible transitions between yeast and hyphal forms. Morphogenesis is an important factor in C. albicans' lifestyle and pathogenicity (7). Strains that are unable to perform the morphologic switch are hypovirulent in models of systemic candidiasis (37,38).…”

“…The compound S-8 was synthesized in our laboratory and was characterized by nuclear magnetic resonance (NMR) analysis, boiling point, and elemental analysis using the same procedure as described previously (7).…”

“…Hyphae and extrapolymeric material are fundamental to the fungal biofilm, due to their pivotal roles in structural integrity and adhesive capacity and their contributions to antifungal resistance. Biofilm formation is an important virulence factor in C. albicans pathogenesis (5); it involves attachment to the host cells and to abiotic surfaces, colonization, and the development of a mature biofilm structure composed of yeast cells, pseudo-and true hyphae, and extracellular matrix (3,(6)(7)(8). In comparison to the susceptibility to fungicides of the planktonic form, the fungicide susceptibility of fungi immobilized in a biofilm is very low.…”

“…In previous studies, we demonstrated a specific antibiofilm effect and molecular mechanism of action of the TZD derivative thiazolidinedione-8 (S-8) in solution against C. albicans (7,9). In addition, S-8 was tested for mammalian toxicity in female ICR mice.…”

Acetylcholine Protects against Candida albicans Infection by Inhibiting Biofilm Formation and Promoting Hemocyte Function in a Galleria mellonella Infection Model

“…To test the hypothesis that ACh impacts C. albicans biofilm formation in vivo, we investigated the expression of two genes known to be important in biofilm formation-HWP1 (the hyphal cell wall protein 1 gene) and ALS3 (the agglutinin-like sequence 3 gene) (28).…”