Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism
| Autor: | Kristina M. DiFranco, Richard W. Scott, Klaudia Falkovsky, Kartikeya Cherabuddi, Lorenzo P. Menzel, Michael J. Costanzo, Rafael Vorona, Damian G. Weaver, Gill Diamond, Jorge A. Masso-Silva, Lisa K. Ryan, Katie B. Freeman, David C. Brice, Hossain Mobaswar Chowdhury, Andrew Malsbary, William N. Ruddick |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Antifungal Agents Science 030106 microbiology Antifungal drug Peptide Host-Derived Cellular Factors Microbial Sensitivity Tests Article Microbiology 03 medical and health sciences chemistry.chemical_compound In vivo Drug Resistance Fungal Candida albicans medicine Humans Propidium iodide Disease Resistance chemistry.chemical_classification Multidisciplinary Membranes biology Complement C4 biology.organism_classification In vitro 3. Good health 030104 developmental biology chemistry Mechanism of action Biochemistry Histatin Host-Pathogen Interactions Medicine medicine.symptom Peptides |
| Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
| ISSN: | 2045-2322 |
| Popis: | Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24 hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|