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Human ß-Defensins Kill Candida albicans in an Energy-Dependent and Salt-Sensitive Manner without Causing Membrane Disruption

Departments of Oral Biology,¹ Restorative Dentistry, School of Dental Medicine,² Department of Biostatistics, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, New York 14214³

Received 18 April 2006/ Returned for modification 17 June 2006/ Accepted 19 October 2006

Human ß-defensin 2 (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 to 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 Candida albicans membrane integrity. Incubation of calcein-loaded C. albicans cells with a dose of hBD-2 lethal for 90% of the strains tested (LD₉₀) resulted in a maximal dye efflux of only 10.3% ± 2.8% at 90 min, similar to that induced by Hst 5. In contrast, an LD₉₀ 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 hBD-3 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 of 0.8 µM, showing energy-independent mechanisms at higher doses. C. glabrata resistance to Hst 5, hBD-2, and hBD-3 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 were additive, while the index of interaction between Hst 5 and hBD-3 was 0.717 (P < 0.05). Thus, the candidacidal action of hBD-2 shows many similarities to that of Hst 5 in terms of salt sensitivity, ion selectivity, and energy requirements while hBD-3 exhibits biphasic concentration-dependent mechanisms of candidacidal action complementary to those of Hst 5.

Published ahead of print on 30 October 2006.

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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]