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Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata

Department of Oral Biology, School of Dental Medicine, University at Buffalo, Foster Hall Buffalo, NY 14214, USA
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J. Fungi 2020, 6(3), 124; https://doi.org/10.3390/jof6030124
Received: 29 June 2020 / Revised: 22 July 2020 / Accepted: 29 July 2020 / Published: 31 July 2020
(This article belongs to the Special Issue Antifungal Peptides 2020)
Histatin 5 (Hst 5) is an antimicrobial peptide produced in human saliva with antifungal activity for opportunistic pathogen Candida albicans. Hst 5 binds to multiple cations including dimerization-inducing zinc (Zn2+), although the function of this capability is incompletely understood. Hst 5 is taken up by C. albicans and acts on intracellular targets under metal-free conditions; however, Zn2+ is abundant in saliva and may functionally affect Hst 5. We hypothesized that Zn2+ binding would induce membrane-disrupting pores through dimerization. Through the use of Hst 5 and two derivatives, P113 (AA 4-15 of Hst 5) and Hst 5ΔMB (AA 1-3 and 15-19 mutated to Glu), we determined that Zn2+ significantly increases killing activity of Hst 5 and P113 for both C. albicans and Candida glabrata. Cell association assays determined that Zn2+ did not impact initial surface binding by the peptides, but Zn2+ did decrease cell association due to active peptide uptake. ATP efflux assays with Zn2+ suggested rapid membrane permeabilization by Hst 5 and P113 and that Zn2+ affinity correlates to higher membrane disruption ability. High-performance liquid chromatography (HPLC) showed that the higher relative Zn2+ affinity of Hst 5 likely promotes dimerization. Together, these results suggest peptide assembly into fungicidal pore structures in the presence of Zn2+, representing a novel mechanism of action that has exciting potential to expand the list of Hst 5-susceptible pathogens. View Full-Text
Keywords: Candida albicans; Candida glabrata; Histatin 5; P113; zinc; membrane disruption Candida albicans; Candida glabrata; Histatin 5; P113; zinc; membrane disruption
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MDPI and ACS Style

Norris, H.L.; Kumar, R.; Ong, C.Y.; Xu, D.; Edgerton, M. Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata. J. Fungi 2020, 6, 124. https://doi.org/10.3390/jof6030124

AMA Style

Norris HL, Kumar R, Ong CY, Xu D, Edgerton M. Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata. Journal of Fungi. 2020; 6(3):124. https://doi.org/10.3390/jof6030124

Chicago/Turabian Style

Norris, Hannah L.; Kumar, Rohitashw; Ong, Chih Y.; Xu, Ding; Edgerton, Mira. 2020. "Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in C. albicans and C. glabrata" J. Fungi 6, no. 3: 124. https://doi.org/10.3390/jof6030124

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