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J. Fungi 2018, 4(1), 30; https://doi.org/10.3390/jof4010030

Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis

1
Department of Oral Biology, University of Florida College of Dentistry, 1600 SW Archer Road, Gainesville, FL 32610, USA
2
Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA
3
Fox Chase Chemical Diversity Center, Inc., Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA
*
Author to whom correspondence should be addressed.
Current Address: Bengal School of Technology—College of Pharmacy, Chinsurah, Hooghly 712102, West Bengal, India.
Received: 6 February 2018 / Revised: 21 February 2018 / Accepted: 24 February 2018 / Published: 27 February 2018
(This article belongs to the Special Issue Antifungal Peptides)
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Abstract

Invasive candidiasis caused by Candida albicans and non-albicans Candida (NAC) present a serious disease threat. Although the echinocandins are recommended as the first line of antifungal drug class, resistance to these agents is beginning to emerge, demonstrating the need for new antifungal agents. Host defense peptides (HDP) exhibit potent antifungal activity, but as drugs they are difficult to manufacture efficiently, and they are often inactivated by serum proteins. HDP mimetics are low molecular weight non-peptide compounds that can alleviate these problems and were shown to be membrane-active against C. albicans and NAC. Here, we expand upon our previous works to describe the in vitro and in vivo activity of 11 new HDP mimetics that are active against C. albicans and NAC that are both sensitive and resistant to standard antifungal drugs. These compounds exhibit minimum inhibitory/fungicidal concentration (MIC/MFC) in the µg/mL range in the presence of serum and are inhibited by divalent cations. Rapid propidium iodide influx into the yeast cells following in vitro exposure suggested that these HDP mimetics were also membrane active. The lead compounds were able to kill C. albicans in an invasive candidiasis CD-1 mouse model with some mimetic candidates decreasing kidney burden by 3–4 logs after 24 h in a dose-dependent manner. The data encouraged further development of this new anti-fungal drug class for invasive candidiasis. View Full-Text
Keywords: defensin; membrane-activity; Candida; peptide mimetics defensin; membrane-activity; Candida; peptide mimetics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Chowdhury, M.H.; Ryan, L.K.; Cherabuddi, K.; Freeman, K.B.; Weaver, D.G.; Pelletier, J.C.; Scott, R.W.; Diamond, G. Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis. J. Fungi 2018, 4, 30.

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