Encapsulation of antifungals in micelles protects Candida albicans during gall-bladder infection

Hsieh, Shih-Hung and Brunke, Sascha and Brock, Matthias (2017) Encapsulation of antifungals in micelles protects Candida albicans during gall-bladder infection. Frontiers in Microbiology, 8 . p. 117. ISSN 1664-302X

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Abstract

Candida albicans is a dimorphic fungus that colonizes human mucosal surfaces with the potential to cause life-threatening invasive candidiasis. Studies on systemic candidiasis in a murine infection model using in vivo real-time bioluminescence imaging revealed persistence of C. albicans in the gall bladder under antifungal therapy. Preliminary analyses showed that bile conferred resistance against a wide variety of antifungals enabling survival in this cryptic host niche. Here, bile and its components were studied for their ability to reduce antifungal efficacy in order to elucidate the underlying mechanism of protection. While unconjugated bile salts were toxic to C. albicans, taurine, or glycine conjugated bile salts were well tolerated and protective against caspofungin and amphotericin B when exceeding their critical micellar concentration. Microarray experiments indicated that upregulation of genes generally known to mediate antifungal protection is not involved in the protection process. In contrast, rhodamine 6G and crystal violet in- and efflux experiments indicated encapsulation of antifungals in micelles, thereby reducing their bioavailability. Furthermore, farnesol sensing was abolished in the presence of conjugated bile salts trapping C. albicans cells in the hyphal morphology. This suggests that bioavailability of amphiphilic and hydrophobic compounds is reduced in the presence of bile. In contrast, small and hydrophilic molecules, such as cycloheximide, flucytosine, or sodium azide kept their antifungal properties. We therefore conclude that treatment of gall bladder and bile duct infections is hampered by the ability of bile salts to encapsulate antifungals in micelles. As a consequence, treatment of gall bladder or bile duct infections should favor the use of small hydrophilic drugs that are not solubilised in micelles.

Item Type: Article
Additional Information: This Document is Protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission.
Keywords: Conjugated bile salts, Caspofungin, Farnesol, Rhodamine 6G, Critical micelle concentration
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.3389/fmicb.2017.00117
Depositing User: Eprints, Support
Date Deposited: 14 Mar 2017 10:01
Last Modified: 12 Oct 2017 22:26
URI: http://eprints.nottingham.ac.uk/id/eprint/41295

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