Lattice_grid_med
Powered by LatticeGrid

Search Enter term and hit return. Use '*' for as a wildcard.
Menzel LP, Chowdhury HM, Masso-Silva JA, Ruddick W, Falkovsky K, Vorona R, Malsbary A, Cherabuddi K, Ryan LK, DiFranco KM, Brice DC, Costanzo MJ, Weaver D, Freeman KB, Scott RW, Diamond G
Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism
Sci Rep (2017) 7:4353.
Abstract
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.
MeSH terms
Note
Publication Date: 2017-06-28.
PMCID: PMC5489528
Back
Last updated on Wednesday, September 06, 2017