Histatin 5-Spermidine Conjugates Have Enhanced Fungicidal Activity and Efficacy as a Topical Therapeutic for Oral Candidiasis

Tati, Swetha; Li, Rui; Puri, Sumant; Kumar, Rishikesh; Davidow, Peter; Edgerton, Mira

doi:10.1128/aac.01851-13

Cited by 30 publications

(40 citation statements)

References 54 publications

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“…AMPs have many potential uses in treatment of complex infections, and their mode of action can be exploited for the generation of novel antifungal molecules. Various applications of human and nonhuman AMPs show the effectiveness of small peptides against the human-pathogenic fungus C. albicans (62,83,86,87). Recently, different AMP resistance mechanisms that allow C. albicans to become either a successful commensal or a human fungal pathogen were discovered (15, 17, 54-56, 61, 88).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an Hst 5-spermidine conjugate has been developed, which enhanced fungicidal activity compared to nonconjugated Hst 5 (83). It is known that Hst 5 utilizes the polyamine transporters Dur3 and Dur31 for its uptake in C. albicans (16); therefore, the Hst 5 peptide (Hst 5 with amino acids 4 to 15 [Hst 5 [4][5][6][7][8][9][10][11][12][13][14][15] ]) conjugated with a GGG linker and spermidine was rapidly taken up, leading to higher in vitro and in vivo candicidal activity than with nonconjugated Hst 5 (83). Collectively, these results suggest that the development and investigation of AMP conjugates could lead to promising new antifungals.…”

Section: Amps: New Antifungal Agents For Therapy?mentioning

confidence: 99%

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Interplay between Candida albicans and the Antimicrobial Peptide Armory

2014

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Antimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungus Candida albicans colonizes different host niches as part of the normal human microbiota. Proliferation of C. albicans is regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host, C. albicans has developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms prevent C. albicans from the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack and C. albicans resistance mechanisms and current developments in the use of AMPs as antifungal agents.

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Section: Discussionmentioning

confidence: 99%

Section: Amps: New Antifungal Agents For Therapy?mentioning

confidence: 99%

Interplay between Candida albicans and the Antimicrobial Peptide Armory

2014

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“…Thus, C. albicans cells in the oral environment that better transport and accumulate Hst 5 (due to activation of Cek1 MAPK) are likely to have even higher sensitivity to Hst 5 than those in in vitro conditions. In this regard, we found that increasing in vitro killing of Hst 5 conjugates by 50% resulted in a more than four-log-fold reduction in fungal tongue burden in murine oropharyngeal candidiasis (OPC) (33). Similar animal experiments are needed to test the effects of Cek1 activation in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…7C). To examine the dynamics of early uptake of Hst 5 in cells exposed to P-Cek1 conditions, we measured propidium iodide (PI) uptake visualized by time-lapse confocal microscopy since intracellular PI is a measure of cell death and directly relates to levels of intracellular Hst 5 (33). C. albicans pretreated with GlcNAc at 37°C showed 21% PI-positive cells after 6 min, compared with only 7% PI-positive cells for those cells pretreated with Glc at 30°C (Fig.…”

Section: Figmentioning

confidence: 99%

Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

Puri

Tati

et al. 2015

Antimicrob Agents Chemother

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Candida albicans is a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC. C. albicans senses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either by N-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility of C. albicans cells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility in C. albicans. Candida albicans is the major etiological organism of oral candidiasis (thrush) in individuals whose immune system is impaired. Naturally occurring antimicrobial peptides, such as defensins and histatins, are promising candidates for the treatment of fungal infections because of their distinct mechanism of action from conventional azole and polyene-based antifungal drugs (1). Salivary histatin 5 (Hst 5) is a fungicidal histidine-rich protein constitutively produced by human salivary gland cells, with physiological concentrations in saliva ranging from 10 to 30 M (2). Hst 5 initially binds to the C. albicans cell wall followed by active translocation into the cytosol by Dur3 and Dur31 polyamine transporters (3). Although Hst 5 appears to have several intracellular targets (4), it ultimately induces selective leakage of small intracellular ions and nucleotides, causing gradual cell death (4).The oral cavity is a challenging environment for fungal colonization due to wide fluctuations in temperature, tonicity, and osmolarity. C. albicans senses environmental changes through its membrane sensors that elicit responses through various signaling pathways, one of the most important being mitogen-activated protein kinase (MAPK) signal transduction pathways (5). Four MAPK pathways have been identified in C. albicans: the highosmolarity glycerol (HOG) pathway, the cell wall integrity Mkc1 pathway, and the Cek1 and Cek2 pathways. The HOG MAPK network is involved in adaptation to both osmotic and oxidative stresses (6-11), as well as heavy metal stresses (11). We found that Hst 5 treatment of C. albicans cells induced rapid activation of the Hog1 pathway (12), related to Hst 5 induction of cellular osmotic stress. C. albicans cells that were first subjected to osmotic stress, to induce Hog1 phosphorylation, became resistant to Hs...

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“…It has recently been shown that cellular uptake is enhanced by conjugation of the active fragment of Hst 5 (shown outlined by a broken line in Fig. 1) with the polyamine spermidine at either the N or C terminus (39). These conjugates were highly effective as topical therapeutics in a murine model of oral candidiasis compared to the original peptide.…”

Section: Binding and Uptake Of Hstmentioning

confidence: 97%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.

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Histatin 5-Spermidine Conjugates Have Enhanced Fungicidal Activity and Efficacy as a Topical Therapeutic for Oral Candidiasis

Cited by 30 publications

References 54 publications

Interplay between Candida albicans and the Antimicrobial Peptide Armory

Interplay between Candida albicans and the Antimicrobial Peptide Armory

Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

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