scholarly journals Scaffold diversity for enhanced activity of glycosylated inhibitors of fungal adhesion

2020 ◽  
Vol 11 (12) ◽  
pp. 1386-1401
Author(s):  
Harlei Martin ◽  
Tara Somers ◽  
Mathew Dwyer ◽  
Ryan Robson ◽  
Frederick M. Pfeffer ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Fungal Pathogen ◽  
Fungal Adhesion ◽  
Enhanced Activity ◽  
Scaffold Diversity

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

scholarly journals Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

2020 ◽  
Author(s):  
Tobias Krämer ◽  
kevin kavanagh ◽  
Trinidad Velasco-Torrijos ◽  
Harlei Martin ◽  
Tara Somers ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Surface ◽  
Conformational Analysis ◽  
Fungal Pathogens ◽  
Yeast Cells ◽  
Hospital Acquired Infections ◽  
Fungal Adhesion ◽  
Buccal Epithelial Cells ◽  
Scaffold Diversity ◽  
Hospital Acquired

<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>

scholarly journals Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

2020 ◽  
Author(s):  
Tobias Krämer ◽  
kevin kavanagh ◽  
Trinidad Velasco-Torrijos ◽  
Harlei Martin ◽  
Tara Somers ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Surface ◽  
Conformational Analysis ◽  
Fungal Pathogens ◽  
Yeast Cells ◽  
Hospital Acquired Infections ◽  
Fungal Adhesion ◽  
Buccal Epithelial Cells ◽  
Scaffold Diversity ◽  
Hospital Acquired

<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>

scholarly journals pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans

2017 ◽  
Vol 8 ◽  
Author(s):  
Julien Chaillot ◽  
Faiza Tebbji ◽  
Carlos García ◽  
Hugo Wurtele ◽  
René Pelletier ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Pathogen ◽  
Human Fungal Pathogen

scholarly journals Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis

2015 ◽  
Vol 83 (7) ◽  
pp. 2614-2626 ◽  
Author(s):  
Rohitashw Kumar ◽  
Darpan Saraswat ◽  
Swetha Tati ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Oral Candidiasis ◽  
Oral Microbiome ◽  
Proteinase Activity ◽  
Adhesion Properties ◽  
Content Type ◽  
Oral Epithelial Cells ◽  
Oral Epithelial ◽  
Cell Cell

Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually withC. albicanscells overexpressing Sap6 (SAP6OE and a Δsap8strain) had thicker fungal plaques and more severe oral infection, while infection with the Δsap6strain was attenuated. These hypervirulent strains had highly aggregative colony structurein vitroand higher secreted proteinase activity; however, the levels of proteinase activity ofC. albicansSaps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6OE and Δsap8cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increasedC. albicansadhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.

scholarly journals A Biphasic Innate Immune MAPK Response Discriminates between the Yeast and Hyphal Forms of Candida albicans in Epithelial Cells

2010 ◽  
Vol 8 (3) ◽  
pp. 225-235 ◽  
Author(s):  
David L. Moyes ◽  
Manohursingh Runglall ◽  
Celia Murciano ◽  
Chengguo Shen ◽  
Deepa Nayar ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Innate Immune

scholarly journals An Efficient, Rapid, and Recyclable System for CRISPR-Mediated Genome Editing in Candida albicans

mSphere ◽  
2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Namkha Nguyen ◽  
Morgan M. F. Quail ◽  
Aaron D. Hernday
Keyword(s):  
Candida Albicans ◽  
Genome Editing ◽  
Fungal Pathogen ◽  
Gene Knockout ◽  
Strain Engineering ◽  
Molecular Genetic Analysis ◽  
Content Type ◽  
Highly Efficient ◽  
Discovery Research ◽  
Gene Knockouts

ABSTRACT Candida albicans is the most common fungal pathogen of humans. Historically, molecular genetic analysis of this important pathogen has been hampered by the lack of stable plasmids or meiotic cell division, limited selectable markers, and inefficient methods for generating gene knockouts. The recent development of clustered regularly interspaced short palindromic repeat(s) (CRISPR)-based tools for use with C. albicans has opened the door to more efficient genome editing; however, previously reported systems have specific limitations. We report the development of an optimized CRISPR-based genome editing system for use with C. albicans. Our system is highly efficient, does not require molecular cloning, does not leave permanent markers in the genome, and supports rapid, precise genome editing in C. albicans. We also demonstrate the utility of our system for generating two independent homozygous gene knockouts in a single transformation and present a method for generating homozygous wild-type gene addbacks at the native locus. Furthermore, each step of our protocol is compatible with high-throughput strain engineering approaches, thus opening the door to the generation of a complete C. albicans gene knockout library. IMPORTANCE Candida albicans is the major fungal pathogen of humans and is the subject of intense biomedical and discovery research. Until recently, the pace of research in this field has been hampered by the lack of efficient methods for genome editing. We report the development of a highly efficient and flexible genome editing system for use with C. albicans. This system improves upon previously published C. albicans CRISPR systems and enables rapid, precise genome editing without the use of permanent markers. This new tool kit promises to expedite the pace of research on this important fungal pathogen.

Sign in / Sign up

Export Citation Format

Share Document