Histatin 5 Metallopeptides and Their Potential against Candida albicans Pathogenicity and Drug Resistance

Zolin, Gabriela Vieira Silva; Fonseca, Fauller Henrique da; Zambom, Carolina Reis; Garrido, Saulo Santesso

doi:10.3390/biom11081209

Cited by 12 publications

(14 citation statements)

References 97 publications

(248 reference statements)

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“…Metal availability and metal binding have a profound impact on Hist-5 structure and activity. 39, 40 making retention of those properties crucial when developing modified Hist-5 peptides for study. Previous studies have utilized fluorescein or rhodamine to label Hist-5 to study peptide uptake and intracellular targets.…”

Section: Resultsmentioning

confidence: 99%

Zinc binding inhibits cellular uptake and antifungal activity of Histatin-5 in Candida albicans

Campbell

Gao

Anand

et al. 2022

Preprint

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Histatin-5 (Hist-5) is a polycationic, histidine-rich antimicrobial peptide with potent antifungal activity against the opportunistic fungal pathogen Candida albicans. Hist-5 has the ability to bind metals in vitro and metals have been shown to alter the fungicidal activity of the peptide. Previous reports on the effect of Zn2+ on Hist-5 activity have been varied and seemingly contradictory. Here we present data elucidating the dynamic role Zn2+ plays as an inhibitory switch to regulate Hist-5 fungicidal activity. A novel fluorescently labeled Hist-5 peptide (Hist-5*) was developed to visualize changes in internalization and localization of the peptide as a function of metal availability in the growth medium. Hist-5* was verified for use as a model peptide and retained antifungal activity and mode of action similar to native Hist-5. Cellular growth assays showed that Zn2+ had a concentration-dependent inhibitory effect on Hist-5 antifungal activity. Imaging by confocal microscopy revealed that equimolar concentrations of Zn2+ kept the peptide localized along the cell periphery rather than internalizing, thus preventing cytotoxicity and membrane disruption. However, the Zn-induced decrease in Hist-5 activity and uptake was rescued by decreasing Zn2+ availability upon addition of a metal chelator EDTA or S100A12, a Zn-binding protein involved in the innate immune response. These results lead us to suggest a model wherein commensal C. albicans may exist in harmony with Hist-5 at concentrations of Zn2+ that inhibit peptide internalization and antifungal activity. Activation of host immune processes that initiate Zn-sequestering mechanisms of nutritional immunity could trigger Hist-5 internalization and cell killing.

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Section: Resultsmentioning

confidence: 99%

Zinc binding inhibits cellular uptake and antifungal activity of Histatin-5 in Candida albicans

Campbell

Gao

Anand

et al. 2022

Preprint

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“…Hst5 binds to the metal as well [ 24 ]. Hst5 stability against protease is improved by the presence of iron, copper, zinc, and nickel [ 25 ]. In vitro studies have revealed that Hst5 increases fungal hydrolysis by binding to host zinc [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Hst5 stability against protease is improved by the presence of iron, copper, zinc, and nickel [ 25 ]. In vitro studies have revealed that Hst5 increases fungal hydrolysis by binding to host zinc [ 25 , 26 ]. In vitro studies have also shown that Hst5 has a synergistic lethal impact on Candida species when combined with AMPs such lactoferrin and defensin, which are found in the female vaginal tract [ 27 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Liano et al [ 6 ] reported that Hst5 is a powerful antifungal protein in a murine vaginal candidiasis model. Hst5 is a potent peptide because their proteolytic fragments called P-113 retain their anti-candidal activity and do not easily break, but they can be broken down by environmental factors, especially in in vivo conditions [ 25 ]. It has also been established that there is a particular Hst5 binding domain on the C .…”

Section: Discussionmentioning

confidence: 99%

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Salivary Histatin 5 Level in Women with Vaginal Candidiasis

Şenyuva

Koca

Çoban

et al. 2022

International Journal of Clinical Practice

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Histatins (Hsts) are considered a prominent member of antimicrobial peptides rich in histidine, bearing antifungal activity against Candida species. Hst5 is the most effective among them. Although Hst5 is not found in the cervicovaginal fluid, it has been detected in the human serum. Saliva acts as a mirror, reflecting the cause and effect relationship between several diseases. We aimed to show the salivary Hst5 levels with vaginal candidiasis. Women in the reproductive age group (18–50 years) were enrolled in the study. Patients and controls were classified based on the presence or absence of vaginal discharge suggestive of candidiasis, respectively. Vaginal and salivary samples were collected from all the women. Vaginal samples were cultured for the growth of Candida species. Salivary samples were tested by protein electrophoresis to detect Hst5 levels, and the results were compared between the two groups. A total of 80 women were included in this study. The mean age of women in vaginal candidiasis and control groups was 34.25 ± 8.06 and 36.83 ± 7.29 years, respectively. Candida species were isolated from the vaginal samples of the patient group (34 C. albicans, 6 non-Candida albicans) but not from the control group. Hst5 levels in the patient and control group were found to be 0.0571 ± 0.003 ng/mL and 0.0641 ± 0,0031 ng/mL, respectively. Hst5 levels were found to be significantly lower in the vaginal candidiasis group ( p = 0.001 ). We conclude that decreased salivary Hst5 levels in women are associated with vaginal candidiasis. Candida infection is a cause or result of lower salivary Hst5 levels, and it may be an important finding for the etiopathogenesis, diagnosis, and treatment of the disease, but further analysis is needed.

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“…They were first identified in 1988 by Oppenheim et al ( 77 ) in human parotid secretion. Within the family, histatin-1,−3 and−5 are the major and most widely studied members and have been shown to exhibit antibacterial, antifungal and wound healing properties ( 77 , 78 ). Histatin-1 and−3 are encoded by HTN1 and HTN3 genes, respectively, and histatin-5 is a proteolytic product of histatin-3 ( 148 ).…”

Section: Spectrum and Characteristics Of Hdps At Ocular Surfacementioning

confidence: 99%

Host Defense Peptides at the Ocular Surface: Roles in Health and Major Diseases, and Therapeutic Potentials

et al. 2022

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Sight is arguably the most important sense in human. Being constantly exposed to the environmental stress, irritants and pathogens, the ocular surface – a specialized functional and anatomical unit composed of tear film, conjunctival and corneal epithelium, lacrimal glands, meibomian glands, and nasolacrimal drainage apparatus – serves as a crucial front-line defense of the eye. Host defense peptides (HDPs), also known as antimicrobial peptides, are evolutionarily conserved molecular components of innate immunity that are found in all classes of life. Since the first discovery of lysozyme in 1922, a wide range of HDPs have been identified at the ocular surface. In addition to their antimicrobial activity, HDPs are increasingly recognized for their wide array of biological functions, including anti-biofilm, immunomodulation, wound healing, and anti-cancer properties. In this review, we provide an updated review on: (1) spectrum and expression of HDPs at the ocular surface; (2) participation of HDPs in ocular surface diseases/conditions such as infectious keratitis, conjunctivitis, dry eye disease, keratoconus, allergic eye disease, rosacea keratitis, and post-ocular surgery; (3) HDPs that are currently in the development pipeline for treatment of ocular diseases and infections; and (4) future potential of HDP-based clinical pharmacotherapy for ocular diseases.

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Histatin 5 Metallopeptides and Their Potential against Candida albicans Pathogenicity and Drug Resistance

Cited by 12 publications

References 97 publications

Zinc binding inhibits cellular uptake and antifungal activity of Histatin-5 in Candida albicans

Zinc binding inhibits cellular uptake and antifungal activity of Histatin-5 in Candida albicans

Salivary Histatin 5 Level in Women with Vaginal Candidiasis

Host Defense Peptides at the Ocular Surface: Roles in Health and Major Diseases, and Therapeutic Potentials

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