V体育2025版 - Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. VSports app下载.

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2014;58(2):756-66.
doi: 10.1128/AAC.01851-13. Epub 2013 Nov 18.

Histatin 5-spermidine conjugates have enhanced fungicidal activity and efficacy as a topical therapeutic for oral candidiasis

Swetha Tati  1 , Rui Li, Sumant Puri, Rohitashw Kumar, Peter Davidow, Mira Edgerton
Affiliations

Histatin 5-spermidine conjugates have enhanced fungicidal activity and efficacy as a topical therapeutic for oral candidiasis

Swetha Tati et al. Antimicrob Agents Chemother. 2014.

VSports在线直播 - Abstract

Oropharyngeal candidiasis (OPC) is caused by the opportunistic fungi Candida albicans and is prevalent in immunocompromised patients, individuals with dry mouth, or patients with prolonged antibiotic therapies that reduce oral commensal bacteria. Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. However, Hsts are rapidly degraded in vivo, limiting their usefulness as therapeutic agents despite their lack of toxicity VSports手机版. We constructed a conjugate peptide using spermidine (Spd) linked to the active fragment of Hst 5 (Hst 54-15), based upon our findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity. We found that Hst 54-15-Spd was significantly more effective in killing C. albicans and Candida glabrata than Hst 5 alone in both planktonic and biofilm growth and that Hst 54-15-Spd retained high activity in both serum and saliva. Hst 54-15-Spd was not bactericidal against streptococcal oral commensal bacteria and had no hemolytic activity. We tested the effectiveness of Hst 54-15-Spd in vivo by topical application to tongue surfaces of immunocompromised mice with OPC. Mice treated with Hst 54-15-Spd had significant clearance of candidal tongue lesions macroscopically, which was confirmed by a 3- to 5-log fold reduction of C. albicans colonies recovered from tongue tissues. Hst 54-15-Spd conjugates are a new class of peptide-based drugs with high selectivity for fungi and potential as topical therapeutic agents for oral candidiasis. .

PubMed Disclaimer

Figures (V体育安卓版)

FIG 1
FIG 1
Hst 5 and Spd conjugates have higher candidacidal activities towards both C. albicans and C. glabrata. Susceptibility of C. albicans and C. glabrata was tested using candidacidal assays. (A) C. albicans cells (CAF4-2) were exposed to Spd, Hst 5, Hst 54–15, Spd-Hst 54–15, and Hst 54–15-Spd (7.5 to 31 μM), and the percentage of killing was calculated. Both Spd-Hst 54–15 and Hst 54–15-Spd showed significantly (P < 0.05) higher candidacidal activity in C. albicans than Hst 5. (B) For C. glabrata, three wild-type strains (Cg 931010, 90032, and 90030) were exposed to Hst 54–15-Spd and Hst 5. Candidacidal activity of Hst 54–15-Spd against three strains of C. glabrata was increased by at least 2 times compared with Hst 5.
FIG 2
FIG 2
Hst 54–15-Spd competes for uptake with spermidine and uses Dur3 transporters in C. albicans. (A) Spermidine (Spd) uptake was calculated for 5 min after addition of BODIPY-X-Spd (100 μM). Hst 54–15-Spd showed significant (P < 0.01) competition for Spd uptake in C. albicans cells in a dose-dependent manner. (B) The C. albicans wild-type (CAF4-2) and Hst 5 uptake transporter-deficient (dur3Δ/Δ, dur31Δ/Δ, and dur3/31Δ/Δ) strains were exposed to Hst 54–15-Spd, and the percentage of killing was calculated. Both the dur3Δ/Δ and the double gene deletion dur3/31Δ/Δ strains were found to be significantly (P < 0.05) less sensitive to Hst 54–15-Spd.
FIG 3
FIG 3
C. albicans and C. glabrata biofilms were more sensitive to Hst 54–15-Spd than Hst 5. Biofilms were formed for 24 h in tissue culture plates, and then Hst 54–15-Spd or Hst 5 (60 μM) was added for 1 h, and the cells were grown further for 24 h. (A) Reduction of biofilm formation in C. albicans was detected in the presence of both Hst 54–15-Spd and Hst 5. (B) Significant (P < 0.005) reduction in C. glabrata biofilms was detected only in the presence of Hst 54–15-Spd (**, P < 0.005; ***, P < 0.0001).
FIG 4
FIG 4
Hst 54–15-Spd is more rapidly internalized by C. albicans cells than Hst 5. (A) Hst 5 or Hst 54–15-Spd was added to C. albicans cells in 10 mM NaPB buffer containing propidium iodide (PI) (5 μg/ml), and images were recorded every 10 s for 30 min using time-lapse confocal microscopy. Total PI-positive cells were measured in a cell population (500 cells) treated with Hst 5 (60 μM) or Hst 54–15-Spd (60 μM). (B) The percentage of PI-positive cells was calculated for each minute after addition of Hst 5 or Hst 54–15-Spd to determine the rate of peptide uptake.
FIG 5
FIG 5
Hst 54–15-Spd showed higher protease-independent candidacidal activity in human whole saliva than Hst 5. Whole saliva with or without added protease inhibitors was incubated with an equal volume (1:1) of fungal cell suspension in NaPB, in which Hst 5 or Hst 54–15-Spd was added to a final peptide concentration of 31 μM. Hst 5 candidacidal activity was significantly increased at both 30°C (***, P < 0.001) and 37°C (*, P < 0.05) in the presence of protease inhibitors; however, Hst 54–15-Spd had significantly (P < 0.05) higher candidacidal activity than Hst 5 in saliva with or without protease inhibitor, showing its activity was protease independent.
FIG 6
FIG 6
Hst 54–15-Spd showed higher candidacidal activity in serum against C. albicans yeast and germinated cells. (A) C. albicans yeast or germinated cells (106 cells) were exposed to Hst 5 or Hst 54–15-Spd without serum. Both Hst 5 and Hst 54–15-Spd 5 were equally active against germinated C. albicans cells compared to yeast cells, although the candidacidal activity of Hst 54–15-Spd 5 was significantly greater (P < 0.001). (B) C. albicans yeast or germinated cells were incubated with serial dilutions of Hst 5 or Hst 54–15-Spd in the presence of 10% serum. Hst 54–15-Spd showed significantly (P < 0.001) higher candidacidal activity at all concentrations in serum compared to Hst 5.
FIG 7
FIG 7
Hst 54–15-Spd peptide is more effective in clearing murine oral candidiasis than Hst 5. (A) Timeline of oral candidiasis infection protocol shows immunosuppression with cortisone (Cort.), infection (infect) with C. albicans, and topical treatment times with peptides (Tx). (B) The clinical appearance of fungal lesions on animal tongues is shown on days 3 and 5 postinfection with C. albicans. (C) CFU per gram of tongue tissues were recovered from C. albicans-infected mice. Hst 54–15-Spd-treated mice (***, P < 0.001) and Hst 5-treated mice (**, P < 0.01) showed significantly reduced tongue CFU compared to PBS-treated animals. (D) Tongue tissues were stained with periodic acid-Schiff stain and viewed at ×10 magnification. The magnified inset shows typical hyphal invasion of the superficial epithelium. Hst 54–15-Spd-treated mouse tongue tissues did not have visible Candida cells and showed normal lingual papillae.
See this image and copyright information in PMC

References

    1. Conti HR, Baker O, Freeman AF, Jang WS, Holland SM, Li RA, Edgerton M, Gaffen SL. 2011. New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome. Mucosal Immunol. 4:448–455. 10.1038/mi.2011.5 - DOI - PMC - PubMed
    1. Kanaguchi N, Narisawa N, Ito T, Kinoshita Y, Kusumoto Y, Shinozuka O, Senpuku H. 2012. Effects of salivary protein flow and indigenous microorganisms on initial colonization of Candida albicans in an in vivo model. BMC Oral Health 12:36. 10.1186/1472-6831-12-36 - DOI - PMC - PubMed
    1. Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, Herwaldt L, Pfaller M, Diekema D. 2003. Attributable mortality of nosocomial candidemia, revisited. Clin. Infect. Dis. 37:1172–1177. 10.1086/378745 - DOI - PubMed
    1. Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, Harrison LH, Seaberg EC, Hajjeh RA, Teutsch SM. 2005. Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect. Control Hosp. Epidemiol. 26:540–547. 10.1086/502581 - DOI - PubMed
    1. Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, Kauffman CA, Hyslop N, Mangino JE, Chapman S, Horowitz HW, Edwards JE, Dismukes WE; Mycoses Study Group NIAID 2003. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin. Infect. Dis. 37:634–643. 10.1086/376906 - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources