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Antimicrob. Agents Chemother. doi:10.1128/AAC.00478-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Human beta-defensins kill Candida albicans in an energy-dependent and salt-sensitive manner without causing membrane disruption

Department of Oral Biology and Restorative Dentistry, School of Dental Medicine; Department of Biostatistics, School of Public Health and Health Professions

^* To whom correspondence should be addressed. Email: edgerto{at}buffalo.edu.

	Abstract

Human -defensins 2 and 3 (hBD-2 and hBD-3) have potent fungicidal activity in the micromolar range. Although little is known about their mechanism of action against Candida species, some similarities with the antifungal mechanism of salivary peptide histatin 5 (Hst 5) seem to exist. Since hBD-2 and hBD-3 have been reported to cause direct disruption of target cell membranes, we compared the effects of hBD-2 and hBD-3 on C. albicans membrane integrity. Incubation of calcein-loaded C. albicans cells with LD₉₀ dose of hBD-2 resulted in maximal dye efflux of only 10.3 ± 2.8% at 90 min, similar to that induced by Hst 5. In contrast, an LD₉₀ dose of hBD-3 more than doubled calcein release from cells, yet did not result in more than 24% of total release, showing that neither peptide caused gross membrane damage. As for Hst 5, killing of C. albicans cells by hBD-2 and hBD-3 was salt-sensitive, however Ca²⁺ and Mg²⁺, inhibited hBD-2, but not hBD3 fungicidal activity. Pretreatment of C. albicans cells with sodium azide resulted in significantly decreased ATP release and susceptibility of cells to hBD-2 and hBD-3. However, hBD-3 killing was partially restored at concentrations 0.8 µM, showing energy independent mechanisms at higher doses. C. glabrata resistance to Hst 5, hBD2 and hBD3 is not a result of loss of expression of cell wall ssa proteins. The candidacidal effects of hBD-2 - hBD-3, and Hst 5 - hBD-2 pairs was additive, while the interaction index between Hst 5 and hBD-3 was 0.717 (p < 0.05). Thus, candidacidal action of hBD-2 shares many similarities with Hst 5 in terms of salt-sensitivity, ion selectivity and energy requirements, while hBD3 exhibits biphasic concentration-dependent mechanisms of candidacidal action complementary to Hst 5.

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• Jang, W. S., Li, X. S., Sun, J. N., Edgerton, M. (2008). The P-113 Fragment of Histatin 5 Requires a Specific Peptide Sequence for Intracellular Translocation in Candida albicans, Which Is Independent of Cell Wall Binding. Antimicrob. Agents Chemother. 52: 497-504 [Abstract] [Full Text]