Anticandida Activity Is Retained in P-113, a 12-Amino-Acid Fragment of Histatin 5

Abstract

Through the analysis of a series of 25 peptides composed of various portions of the histatin 5 sequence, we have identified P-113, a 12-amino-acid fragment of histatin 5, as the smallest fragment that retains anticandidal activity comparable to that of the parent compound. Amidation of the P-113 C terminus increased the anticandidal activity of P-113 approximately twofold. The three histidine residues could be exchanged for three hydrophobic residues, with the fragment retaining anticandidal activity. However, the change of two or more of the five basic (lysine and arginine) residues to uncharged residues resulted in a substantial loss of anticandidal activity. A synthetic D-amino-acid analogue, P-113D, was as active against Candida albicans as the L-amino-acid form. In vitro MIC tests in low-ionic-strength medium showed that P-113 has potent activity against Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis. These results identify P-113 as a potential antimicrobial agent in the treatment of oral candidiasis.

Susceptibility of oral bacteria to an antimicrobial decapeptide

“…Many synthetic analogues of these peptides have been created in attempts to improve the antimicrobial activity of some of these naturally occurring antibacterial peptides (Wade et al, 1992;Tamamura et al, 1995;Helmerhorst et al, 1997;Fuchs et al, 1998;Chen et al, 2000;Mosca et al, 2000;Rothstein et al, 2001). For example, Dhvar 5, an analogue of histatin 5, one of the antimicrobial histatin peptides that are derived from saliva (Helmerhorst et al, 1999;Mickels et al, 2001) and IB-367, an analogue of protegrins, antimicrobial peptides that were isolated from porcine leukocytes (Zhao et al, 1994;Chen et al, 2000;Mosca et al, 2000), are more effective in inhibiting bacterial growth and are synthesized more easily than their native counterparts.…”

“…the presence of arginine and lysine residues and can be grouped into four or five different structural categories. These include: (a) cysteine-rich, amphiphilic â-sheet peptides (AE-and â-defensins, protegrins and tachyplesins); (b) cysteine-disulfide ring peptides with or without amphiphilic tails (bactenecin, ranalexin and brevinins); (c) amphiphilic AE-helical peptides without cysteine (magainins and cecropins); and (d) linear peptides (Bac 5, Bac 7, PR39 and indolicidin) with one or two predominant amino acids (proline or tryptophan) (Hancock et al, 1995;Hancock, 1997b;Hancock & Lehrer, 1998;Henderson et al, 1998).Many synthetic analogues of these peptides have been created in attempts to improve the antimicrobial activity of some of these naturally occurring antibacterial peptides (Wade et al, 1992;Tamamura et al, 1995;Helmerhorst et al, 1997;Fuchs et al, 1998;Chen et al, 2000;Mosca et al, 2000;Rothstein et al, 2001). For example, Dhvar 5, an analogue of histatin 5, one of the antimicrobial histatin peptides that are derived from saliva (Helmerhorst et al, 1999;Mickels et al, 2001) and IB-367, an analogue of protegrins, antimicrobial peptides that were isolated from porcine leukocytes (Zhao et al, 1994;Chen et al, 2000;Mosca et al, 2000), are more effective in inhibiting bacterial growth and are synthesized more easily than their native counterparts.…”

Candida albicans biofilm formation on peptide functionalized polydimethylsiloxane

“…The minimal inhibitory concentrations (MICs) were determined using LYM broth (5 mM KCl, 5.6 mM Na 2 HPO 4 , 0.5 mM MgSO 4 , 1.0 mM sodium citrate, 0.4 mg l -1 ZnCl 2 , 2.0 mg l according to Rothstein et al (2001). Glucose, an amino acid mixture, and a vitamin mixture were added as well according to the manufacturer's instructions.…”

Rapamycin control of exocrine protein levels in saliva after adenoviral vector-mediated gene transfer

“…[27][28][29][30] Antimicrobial peptides encoded by single genes, such as the b-defensins, 31,32 can be introduced into salivary glands by the gene transfer approach used here 7 and are effective in the 1-5 mg/ml concentration range. 31 Similarly, oral candidiasis is relatively common in immunosuppressed (AIDS, transplant) patients, 33,34 and Candidal species are becoming increasingly resistant to azole-type drugs. 34,35 Genes encoding anticandidal peptides, such as the histatins, 7,34 also can be readily introduced into salivary glands.…”

“…31 Similarly, oral candidiasis is relatively common in immunosuppressed (AIDS, transplant) patients, 33,34 and Candidal species are becoming increasingly resistant to azole-type drugs. 34,35 Genes encoding anticandidal peptides, such as the histatins, 7,34 also can be readily introduced into salivary glands. Importantly, a typical course of antimicrobial therapy for oral infections would be for B10-14 days, that is, similar to that shown possible herein with Ad vectors.…”