Candida spp. are a frequent cause of bloodstream infections, with an estimated 50,000 cases and 15,000 deaths at a cost of $2 billion per year in the US. Non-albicans species such as C. parapsilosis, C. krusei, C. tropicalis, C. glabrata and C. auris are emerging as significant causes of systemic infection, especially in vulnerable populations. In many cases, these species have intrinsic resistance to current antifungal drugs which complicates their treatment. Given that relatively few antifungal agents are available and antifungal discovery is lagging, resistance is a major public health concern. Novel antifungal compounds are therefore urgently needed to address this challenge. A key step in the virulence process of Candida spp. is adhesion to host tissues and this step requires specific remodeling of the cell wall. We have recently discovered that clinical isolates of C. parapsilosis grown under conditions that mimic a human host exhibit upregulation of several potential virulence factors, including Phr1 – a fungal cell wall transglycosylase that is required for clinical isolates of C. parapsilosis to adhere to extracellular matrix proteins under fluid shear. Here we report results of our virtual fragment screen of the ZINC database (1.1 million fragments) with the crystal structure of the Phr1 homolog Gas2 from Saccharomyces cerevisiae. Fragments with a binding score of less than -25 kJ/mol (181 compounds) were selected as potential candidates and grouped into four structural families. Docking results were further evaluated based on ligand efficiency (LE) and number of potential hydrogen bonds. Fragments ZINC000049474219 (LE -2.05), ZINC00149427926 (LE -2.08), ZINC0014942792 (LE -2.08) were among the most promising identified. Analysis of docked fragments showed binding in the donor subsite of Gas2 and identified potential π-π and π-CH2 interactions. Commercially available representatives from each family were screened against recombinant Gas2 in an LC-MS assay and a fluid shear assay with C. parapsilosis.

Virtual fragment screen to identify inhibitors of fungal cell wall transglycosylases

ACS Spring Meeting 2021

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