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

Journal of Fungi

Rohitashw Kumar¹  Mira Edgerton¹  HannahL. Norris¹  Ding Xu¹  ChihYean Ong¹ 

[1] Department of Oral Biology, School of Dental Medicine, University at Buffalo, Foster Hall Buffalo, NY 14214, USA;

关键词: Candida albicans;    Candida glabrata;    Histatin 5;    P113;    zinc;    membrane disruption;   

DOI  :  10.3390/jof6030124

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown