Novel keto-alkyl-pyridinium antifungal molecules active in models of in vivo Candida albicans vascular catheter infection and ex vivo Candida auris skin colonization

Sarah R Beattie; Taiwo Esan; Robert Zarnowski; Emily Eix; Jeniel E Nett; David R Andes; Timothy Hagen; Damian J Krysan

doi:10.1101/2023.01.19.524835

Back

Novel keto-alkyl-pyridinium antifungal molecules active in models of in vivo Candida albicans vascular catheter infection and ex vivo Candida auris skin colonization

Preprint

Open access

Novel keto-alkyl-pyridinium antifungal molecules active in models of in vivo Candida albicans vascular catheter infection and ex vivo Candida auris skin colonization

Sarah R Beattie, Taiwo Esan, Robert Zarnowski, Emily Eix, Jeniel E Nett, David R Andes, Timothy Hagen and Damian J Krysan

bioRxiv : the preprint server for biology

01/20/2023

DOI: 10.1101/2023.01.19.524835

PMCID: PMC9882332

PMID: 36711909

Files and links (1)

url

https://doi.org/10.1101/2023.01.19.524835View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

New antifungal therapies are needed for both systemic, invasive infections as well as superficial infections of mucosal and skin surfaces as well as biofilms associated with medical devices. The resistance of biofilm and biofilm-like growth phases of fungi contributes to the poor efficacy of systemic therapies to non-systemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2-16 µg/mL) against medically important yeasts and moulds, including clinical isolates resistant to azoles and/or echinocandins. Furthermore, these keto-alkyl-pyridinium agents retain substantial activity against biofilm phase yeast and have direct activity against hyphal . Although their toxicity precludes use in systemic infections, we found that the keto-alkyl-pyridinium molecules reduce fungal burden in a rat model of vascular catheter infection and reduce colonization in a porcine ex vivo model. These initial pre-clinical data suggest that molecules of this class may warrant further study and development.

Details

Title: Subtitle: Novel keto-alkyl-pyridinium antifungal molecules active in models of in vivo Candida albicans vascular catheter infection and ex vivo Candida auris skin colonization
Creators: Sarah R Beattie
Taiwo Esan
Robert Zarnowski
Emily Eix
Jeniel E Nett
David R Andes
Timothy Hagen
Damian J Krysan
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.01.19.524835
PMID: 36711909
PMCID: PMC9882332
Language: English
Date posted: 01/20/2023
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984364513502771

Metrics

14 Record Views