Antifungal activity of etomidate against growing biofilms of fluconazole-resistant Candida spp. strains, binding to mannoproteins and molecular docking with the ALS3 protein

This study evaluated the effect of etomidate against biofilms of Candida spp. and analysed through molecular docking the interaction of this drug with ALS3, an important protein for fungal adhesion. Three fluconazole-resistant fungi were used: Candida albicans, Candida parapsilosis and Candida tropicalis. Growing biofilms were exposed to etomidate at 31.25–500 µg ml−1. Then, an ALS3 adhesive protein from C. albicans was analysed through a molecular mapping technique, composed of a sequence of algorithms to perform molecular mapping simulation based on classic force field theory. Etomidate showed antifungal activity against growing biofilms of resistant C. albicans, C. parapsilosis and C. tropicalis at all concentrations used in the study. The etomidate coupling analysis revealed three interactions with the residues of interest compared to hepta-threonine, which remained at the ALS3 site. In addition, etomidate decreased the expression of mannoproteins on the surface of C. albicans. These results revealed that etomidate inhibited the growth of biofilms.

Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

<div>Candida albicans is one of the most prevalent fungal pathogens involved in</div><div>hospital acquired infections. It uses adhesins to bind to glycans at the cell surface of epithelial</div><div>cells and thus initiate infection. These interactions can be blocked by synthetic carbohydrates</div><div>(such as compound 1) that mimics the structure of cell surface glycans. Herein we report the</div><div>synthesis of a new series of divalent galactosides featuring aromatic (benzene, squaramides)</div><div>and aliphatic (norbornenes) central scaffolds, with the latter being the first examples of their</div><div>kind as small molecule anti-adhesion glycoconjugates. The evaluation of these compounds as</div><div>inhibitors of adhesion of C. albicans o exfoliated buccal epithelial cells (BECs) revealed that</div><div>galactosides 1 and 6, built on an aromatic core, were the most efficient inhibitors of adhesion,</div><div>displacing up to 36% and 48%, respectively, of yeast cells already attached to the BECs at</div><div>0.138 μM. Conformational analysis of compound 1 identified the preference for a folded </div><div>presentation in the lowest energy conformers. Remarkably, cis-endo-norbornene 21 performed</div><div>comparably to the benzene-core derivatives, highlighting the potential of norbornenes as a new</div><div>class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.</div>

Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

<div>Candida albicans is one of the most prevalent fungal pathogens involved in</div><div>hospital acquired infections. It uses adhesins to bind to glycans at the cell surface of epithelial</div><div>cells and thus initiate infection. These interactions can be blocked by synthetic carbohydrates</div><div>(such as compound 1) that mimics the structure of cell surface glycans. Herein we report the</div><div>synthesis of a new series of divalent galactosides featuring aromatic (benzene, squaramides)</div><div>and aliphatic (norbornenes) central scaffolds, with the latter being the first examples of their</div><div>kind as small molecule anti-adhesion glycoconjugates. The evaluation of these compounds as</div><div>inhibitors of adhesion of C. albicans o exfoliated buccal epithelial cells (BECs) revealed that</div><div>galactosides 1 and 6, built on an aromatic core, were the most efficient inhibitors of adhesion,</div><div>displacing up to 36% and 48%, respectively, of yeast cells already attached to the BECs at</div><div>0.138 μM. Conformational analysis of compound 1 identified the preference for a folded </div><div>presentation in the lowest energy conformers. Remarkably, cis-endo-norbornene 21 performed</div><div>comparably to the benzene-core derivatives, highlighting the potential of norbornenes as a new</div><div>class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.</div>

Yeast Nanometric Scale Oscillations Highlights Fibronectin Induced Changes in C. albicans

Yeast resistance to antifungal drugs is a major public health issue. Fungal adhesion onto the host mucosal surface is still a partially unknown phenomenon that is modulated by several actors among which fibronectin plays an important role. Targeting the yeast adhesion onto the mucosal surface could lead to potentially highly efficient treatments. In this work, we explored the effect of fibronectin on the nanomotion pattern of different Candida albicans strains by atomic force microscopy (AFM)-based nanomotion detection and correlated the cellular oscillations to the yeast adhesion onto epithelial cells. Preliminary results demonstrate that strongly adhering strains reduce their nanomotion activity upon fibronectin exposure whereas low adhering Candida remain unaffected. These results open novel avenues to explore cellular reactions upon exposure to stimulating agents and possibly to monitor in a rapid and simple manner adhesive properties of C. albicans.

Contributions of the Biofilm Matrix to Candida Pathogenesis

In healthcare settings, Candida spp. cause invasive disease with high mortality. The overwhelming majority of cases are associated with the use of critically-needed medical devices, such as vascular catheters. On the surface of these indwelling materials, Candida forms resilient, adherent biofilm communities. A hallmark characteristic of this process is the production of an extracellular matrix, which promotes fungal adhesion and provides protection from external threats. In this review, we highlight the medical relevance of device-associated Candida biofilms and draw attention to the process of Candida-biofilm-matrix production. We provide an update on the current understanding of how biofilm extracellular matrix contributes to pathogenicity, particularly through its roles in the promoting antifungal drug tolerance and immune evasion.

Scaffold diversity for enhanced activity of glycosylated inhibitors of fungal adhesion

Norbornene scaffolds are suitable replacements of aromatic cores in glycosylated inhibitors of adhesion of fungal pathogen Candida albicans to epithelial cells.

Novel Poly(Methyl Methacrylate) Containing Nanodiamond to Improve the Mechanical Properties and Fungal Resistance

Herein we evaluate the effect of nanodiamond (ND) incorporation on the mechanical properties of poly(methyl methacrylate) (PMMA) nanocomposite. Three quantities of ND (0.1, 0.3, and 0.5 wt.%) were tested against the control and zirconium oxide nanoparticles (ZrO). Flexural strength and elastic modulus were measured using a three-point bending test, surface hardness was evaluated using the Vickers hardness test, and surface roughness was evaluated using atomic force microscopy (AFM), while fungal adhesion and viability were studied using Candida albicans. Samples were also analyzed for biofilm thickness and biomass in a saliva-derived biofilm model. All groups of ND-PMMA nanocomposites had significantly greater mean flexural strengths and statistically improved elastic modulus, compared to the control and ZrO groups (P < 0.001). The Vickers hardness values significantly increased compared to the control group (P < 0.001) with 0.3% and 0.5% ND. ND addition also gave significant reduction in fungal adhesion and viability (P < 0.001) compared to the control group. Finally, salivary biofilm formation was markedly reduced compared to the ZrO group. Hence, the incorporation of 0.1–0.5 wt.% ND with auto- polymerized PMMA resin significantly improved the flexural strength, elastic modulus, and surface hardness, and provided considerable fungal resistance.

Microfluidic quantification and separation of yeast based on surface adhesion

Fungal adhesion is fundamental to processes ranging from infections to food production. We developed a microfluidic assay for rapid screening and fractionation of genetically-related yeast based on adhesive properties.