title: Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity.
abstract: The increase in the use of antifungal agents for prophylaxis and therapy has led to the development of antifungal drug resistance. Drug combinations may prevent or delay resistance development. The aim of the present study was to investigate whether naturally and designed cationic antifungal peptides act synergistically with commonly used antimycotics. No enhanced activity was found upon addition of dhvar4, a designed analogue of the human salivary peptide histatin 5, or PGLa to fluconazole or 5-flucytosine, respectively. In contrast, strong synergism of amphotericin B with the peptides was found against several Aspergillus, Candida, and Cryptococcus strains, and against an amphotericin B-resistant C. albicans laboratory mutant in the standardised broth microdilution assays according to the NCCLS standard method M27-T. Amphotericin B showed synergism with dhvar5, another designed analogue of histatin 5, and with magainin 2 against all seven tested strains. Combinations of amphotericin B with histatin 5, dhvar4, and PGLa showed synergism against four of the seven strains. The growth inhibitory activity of amphotericin B was enhanced by sub-MIC concentrations of peptide, but its haemolytic activity remained unaffected, suggesting that its cytotoxicity to host cells was not increased and that peptides may be suitable candidates for combination therapy.
authors.affiliation: Academic Centre for Dentistry, ACTA, Department of Oral Biology, Vrije Universiteit, Amsterdam, The Netherlands. wimvanthof@freeler.nl
authors.forename: W
authors.initials: W
authors.lastname: van't Hof
authors.forename: I M
authors.initials: IM
authors.lastname: Reijnders
authors.forename: E J
authors.initials: EJ
authors.lastname: Helmerhorst
authors.forename: E
authors.initials: E
authors.lastname: Walgreen-Weterings
authors.forename: I M
authors.initials: IM
authors.lastname: Simoons-Smit
authors.forename: E C
authors.initials: EC
authors.lastname: Veerman
authors.forename: A V
authors.initials: AV
authors.lastname: Amerongen
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects / Q000254:growth & development; D002175:Candida / Q000187:drug effects / Q000254:growth & development; D003454:Cryptococcus / Q000187:drug effects / Q000254:growth & development; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology; D005437:Flucytosine / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects* / Q000254:growth & development; D054808:Histatins; D006801:Humans; D054806:Magainins; D008826:Microbial Sensitivity Tests; D012471:Salivary Proteins and Peptides / Q000494:pharmacology*; D029867:Xenopus Proteins
chemical_list: D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; C068075:HTN3 protein, human; D054808:Histatins; D054806:Magainins; D012471:Salivary Proteins and Peptides; D029867:Xenopus Proteins; C045866:peptide-Gly-Leu-amide; C053301:magainin 2 peptide, Xenopus; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine