Journal article
Novel Keto-Alkyl-Pyridinium Antifungal Molecules Active in Models of In Vivo Candida albicans Vascular Catheter Infection and Ex Vivo Candida auris Skin Colonization
Antimicrobial agents and chemotherapy, Vol.67(5), e0008123
05/17/2023
DOI: 10.1128/aac.00081-23
PMCID: PMC10190616
PMID: 37097144
Abstract
New antifungal therapies are needed for both systemic, invasive infections in addition to 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 nonsystemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2 to 16 μg/mL) against medically important yeasts and molds, 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 A. fumigatus. Although their toxicity precludes use in systemic infections, we found that the keto-alkyl-pyridinium molecules reduce Candida albicans fungal burden in a rat model of vascular catheter infection and reduce Candida auris colonization in a porcine ex vivo model. These initial preclinical data suggest that molecules of this class may warrant further study and development for nonsystemic applications.
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 - University of IowaTaiwo Esan - Northern Illinois UniversityRobert Zarnowski - University of Wisconsin–MadisonEmily Eix - University of Wisconsin–MadisonJeniel E Nett - University of Wisconsin–MadisonDavid R Andes - University of Wisconsin–MadisonTimothy Hagen - Northern Illinois UniversityDamian J Krysan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.67(5), e0008123
- DOI
- 10.1128/aac.00081-23
- PMID
- 37097144
- PMCID
- PMC10190616
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R21AI164578, R01AI161973, F32AI145160, R01AI073289; DOI: 10.13039/100000001, name: National Science Foundation, award: CHE-2117776
- Language
- English
- Electronic publication date
- 04/25/2023
- Date published
- 05/17/2023
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984399642502771