Histatin-5 induces the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisae

J Mycol Med. 2018 Mar;28(1):137-142. doi: 10.1016/j.mycmed.2017.11.002. Epub 2017 Dec 6.


Background: Candidiasis is a major opportunistic fungal infection in humans. The low number of antifungal drugs available to treat Candida infections and the increasing incidence of multidrug resistant (MDR) strains point to an urgent need of identifying new therapeutic options. The role of salivary components can provide insights for the development of new methodologies of control.

Objective: The aim of this study was to evaluate the ability of histatin-5, a constitutive immunological peptide present in saliva, in reversing fungal MDR phenotype, using a resistant Saccharomyces cerevisiae strain as model of study.

Results: A total of 2.5μg and 5μg of histatin-5 revealed to be able to chemosensitize (to revert antifungal resistance) a MDR strain to fluconazole impairing its intrinsic resistance. The presence of histatin-5 decreased the strain growth when associated to fluconazole, and also assisted in the retention of rhodamine 6G within cell cytoplasm. The ATPase activity of Pdr5p, an ABC efflux transporter, was significantly reduced up to 65% within physiological concentration of the peptide.

Conclusion: Results revealed that histatin-5 is able to revert MDR phenotype and may be considered a potential alternative MDR inhibitor. Since Pdr5p is homologous to Candida albicans CaCdr1p and CaCdr2p, data obtained might be extrapolated to these transporters, inferring that associating fluconazole and histatin-5 may be a useful tool to circumvent failure treatments of infections caused by Candida MDR strains.

Keywords: Antimicrobial peptide; Candidiasis; Fluconazole; Histatin-5; Multidrug resistance; Yeast.

MeSH terms

  • ATP-Binding Cassette Transporters / drug effects*
  • ATP-Binding Cassette Transporters / genetics
  • Antifungal Agents / pharmacology*
  • Biological Transport
  • Candidiasis / drug therapy
  • Drug Resistance, Multiple, Fungal / drug effects*
  • Drug Resistance, Multiple, Fungal / genetics
  • Fluconazole / pharmacology*
  • Histatins / chemistry
  • Histatins / isolation & purification
  • Histatins / pharmacology*
  • Humans
  • Microbial Sensitivity Tests
  • Rhodamines / analysis
  • Rhodamines / metabolism
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / drug effects*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saliva / chemistry


  • ATP-Binding Cassette Transporters
  • Antifungal Agents
  • Histatins
  • PDR5 protein, S cerevisiae
  • Rhodamines
  • Saccharomyces cerevisiae Proteins
  • rhodamine 6G
  • Fluconazole