Targeting Adhesion in Fungal Pathogen Candida Albicans

Abstract

Fungal infections with increasing resistance to conventional therapies are a growing concern. Candida albicans is a major opportunistic yeast responsible for mucosal and invasive infections. Targeting the initial step of the infection process (i.e., C. albicans adhesion to the host cell) is a promising strategy. A wide variety of molecules can interfere with adhesion processes via an assortment of mechanisms. Herein, we focus on how small molecules disrupt biosynthesis of fungal cell wall components and membrane structure, prevent the localization of GPI-anchor proteins, inhibit production of enzymes involved in adhesion, downregulate genes encoding adhesins and competitively inhibit receptor interactions. As a result, adhesion of C. albicans to host cells is reduced, paving the way to new classes of antifungal agents.

The Synthesis and Evaluation of Multivalent Glycopeptoids as Inhibitors of the Adhesion of Candida albicans

“…In our previous work [ 28 , 29 ] we established that compound 1 and derivatives were not toxic to C. albicans yeast cells at the concentrations used in the current study. Glycoconjugates 3 , featuring multivalent displays of the original lead compound 1 , along with tetra-β-triazolyl-galactoside 15 , were then evaluated for their anti-adhesive properties against C. albicans using several assays.…”

“…In order to install lead compound 1 onto the alkyne-featuring scaffold 2 via the CuAAC reaction, it had to be functionalized with an azido group in a manner that would not compromise its interaction with target proteins in the C. albicans cell wall. Our previous work showed that functionalization of 5-aminobenzene position in compound 1 with a fluorescent label still allowed for the recognition of the digalactoside motifs and localization of the compound at the cell wall in C. albicans [ 28 ]. Thus, 5-amino-isophthalic acid was protected using tert -butoxycabonyl (Boc) anhydride, followed by reaction with propargylamine and TBTU to give compound 4 ( Scheme 1 ).…”

“…Thus, 5-amino-isophthalic acid was protected using tert -butoxycabonyl (Boc) anhydride, followed by reaction with propargylamine and TBTU to give compound 4 ( Scheme 1 ). CuAAC chemistry was used to conjugate the per-acetylated-1-β-azido galactose [ 33 ] moieties to dialkyne 4 to give compound 5 , which was then treated with TFA to remove the N -Boc-protecting group yielding compound 6 [ 28 ]. Reaction with bromoacetyl bromide to give compound 7 and subsequent bromide displacement by treatment with sodium azide gave key azido-functionalized compound 8 [ 29 ].…”

“…Previous research in our group hence screened a small library of synthetic glycoconjugates with various sugars and valencies, and tested their ability to inhibit the adhesion of C. albicans to human BEC. This study showed that the divalent galactoside 1 ( Figure 1 ) was a successful inhibitor of the adhesion of C. albicans to BECs [ 28 ]. Ongoing research in the group is aiming to identify the adhesin on the cell surface of the C. albicans with which this galactosylated compound 1 is interacting.…”

Multivalent Presentations of Glycomimetic Inhibitor of the Adhesion of Fungal Pathogen Candida albicans to Human Buccal Epithelial Cells

“…Candida albicans is an opportunistic pathogenic yeast and is the most prevalent cause of fungal infections worldwide, particularly in hospital-acquired infections. 35 − 37 The yeast is capable of causing a wide range of superficial and systemic infections in the immunocompromised patient, and there is now also growing concern for the coinfection of fungal pathogens in Covid-19 patients. 38 − 40 It is therefore extremely important that new treatments are developed for these fungal infections, some of which are now showing resistance to conventional antifungal therapies.…”