title: Anethole potentiates dodecanol's fungicidal activity by reducing PDR5 expression in budding yeast.
abstract: trans-Anethole (anethole), a major component of anise oil, has a broad antimicrobial spectrum and a weaker antimicrobial potency than other available antibiotics. When combined with polygodial, nagilactone E, and n-dodecanol, anethole has been shown to exhibit synergistic antifungal activity against a budding yeast, Saccharomyces cerevisiae, and a human opportunistic pathogenic yeast, Candida albicans. However, the mechanism underlying this synergistic effect of anethole has not been characterized.
  
  
  
  We studied this mechanism using dodecanol-treated S. cerevisiae cells and focusing on genes related to multidrug efflux.
  
  
  
  Although dodecanol transiently reduced the number of colony forming units, this recovered to levels similar to those of untreated cells with continued incubation beyond 24h. Reverse transcription polymerase chain reaction analysis revealed overexpression of an ATP-binding cassette (ABC) transporter gene, PDR5, in addition to a slight increase in PDR11, PDR12, and PDR15 transcriptions in dodecanol-treated cells. In the presence of anethole, these effects were attenuated and the fungicidal activity of dodecanol was extended. Dodecanol showed longer lasting fungicidal activity against a Δpdr5. In addition, Δpdr3 and Δlge1, lack transcription factors of PDR5 and PDR3, were partly and completely susceptible to dodecanol, respectively. Furthermore, combination of anethole with fluconazole was also found to exhibit synergy on C. albicans.
  
  
  
  These results indicated that although anethole reduced the transcription of several transporters, PDR5 expression was particularly relevant to dodecanol efflux.
  
  
  
  Anethole is expected to be a promising candidate drug for the inhibition of efflux by reducing the transcription of several ABC transporters.
authors.affiliation: Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan. Electronic address: kfujita@sci.osaka-cu.ac.jp.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Fujita
authors.affiliation: Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishikura
authors.affiliation: Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Jono
authors.affiliation: Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan; Advanced Research Institute for Natural Science and Technology, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan; Research Center for Urban Health and Sports, Osaka City University, Sumiyoshi-ku,Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ogita
authors.affiliation: Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, USA.
authors.forename: Isao
authors.initials: I
authors.lastname: Kubo
authors.affiliation: Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000081248:Allylbenzene Derivatives; D000840:Anisoles / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D007851:Dodecanol / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D004718:Saccharomycetales / Q000187:drug effects* / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000081248:Allylbenzene Derivatives; D000840:Anisoles; D000935:Antifungal Agents; D004268:DNA-Binding Proteins; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D007851:Dodecanol; D015725:Fluconazole; C006578:anethole
keywords: Anethole; Antifungal; Dodecanol; Multidrug resistance; PDR5; S. cerevisiae