دورية أكاديمية
أعرض في EDS

Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism.

التفاصيل البيبلوغرافية
العنوان: Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism.
المؤلفون: Menzel LP; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA., Chowdhury HM; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA., Masso-Silva JA; Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, Newark, NJ, 07101, USA., Ruddick W; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA., Falkovsky K; Department of Oral Biology, New Jersey Dental School, Rutgers, Newark, NJ, 07101, USA., Vorona R; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA., Malsbary A; Department of Oral Biology, New Jersey Dental School, Rutgers, Newark, NJ, 07101, USA., Cherabuddi K; Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, 32610, USA., Ryan LK; Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, 32610, USA., DiFranco KM; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA., Brice DC; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA., Costanzo MJ; Beta Pharma, Inc., Princeton, NJ, 08540, USA., Weaver D; Fox Chase Chemical Diversity Center, Doylestown, PA, USA., Freeman KB; Fox Chase Chemical Diversity Center, Doylestown, PA, USA., Scott RW; Fox Chase Chemical Diversity Center, Doylestown, PA, USA., Diamond G; Department of Oral Biology, University of Florida, Gainesville, FL, 32610, USA. gdiamond@dental.ufl.edu.
المصدر: Scientific reports [Sci Rep] 2017 Jun 28; Vol. 7 (1), pp. 4353. Date of Electronic Publication: 2017 Jun 28.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Host-Pathogen Interactions*/genetics , Host-Pathogen Interactions*/immunology, Antifungal Agents/*pharmacology , Host-Derived Cellular Factors/*pharmacology , Membranes/*drug effects , Peptides/*pharmacology, Antifungal Agents/chemistry ; Candida albicans/drug effects ; Candida albicans/genetics ; Candida albicans/metabolism ; Candida albicans/ultrastructure ; Complement C4/immunology ; Disease Resistance ; Drug Resistance, Fungal ; Host-Derived Cellular Factors/chemistry ; Humans ; Microbial Sensitivity Tests ; Peptides/chemistry
مستخلص: 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.
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معلومات مُعتمدة: R44 AI106270 United States AI NIAID NIH HHS
المشرفين على المادة: 0 (Antifungal Agents)
0 (Complement C4)
0 (Host-Derived Cellular Factors)
0 (Peptides)
تواريخ الأحداث: Date Created: 20170630 Date Completed: 20190108 Latest Revision: 20231112
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5489528
DOI: 10.1038/s41598-017-04462-6
PMID: 28659617
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-017-04462-6