Anethole potentiates dodecanol's fungicidal activity by reducing PDR5 expression in budding yeast

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 2; pp. 477 - 484
• Main Authors: Fujita, Ken-ichi, Ishikura, Takayuki, Jono, Yui, Yamaguchi, Yoshihiro, Ogita, Akira, Kubo, Isao, Tanaka, Toshio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2017
• Subjects: ABC transporters; Anethole; anise; Anisoles - pharmacology; antibiotics; Antifungal; Antifungal Agents - pharmacology; antifungal properties; ATP-Binding Cassette Transporters - metabolism; Candida albicans; Candida albicans - drug effects; Candida albicans - metabolism; DNA-Binding Proteins - metabolism; Dodecanol; Dodecanol - pharmacology; drugs; fluconazole; Fluconazole - pharmacology; gene overexpression; genes; humans; Multidrug resistance; oils; PDR5; reverse transcriptase polymerase chain reaction; S. cerevisiae; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Saccharomycetales - drug effects; Saccharomycetales - metabolism; Stem Cells - drug effects; synergism; transcription factors; Transcription Factors - metabolism; yeasts; FIC; ABC; FFC; Antifungal; MIC; Multidrug resistance; MFC; PDR5; CFU; RT-PCR; Dodecanol; Anethole; MFS; PDR; S. cerevisiae
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.09.010

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. •Anethole attenuated expression of dodecanol-induced PDR5 for multidrug exhaust pumps.•Dodecanol showed longer lasting fungicidal activity against Δpdr5 strain.•Combination of anethole with fluconazole showed synergistic effects on C. albicans.