A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering With Fatty Acid Homeostasis

Antimicrob Agents Chemother. 2012 Jun;56(6):2894-907. doi: 10.1128/AAC.05663-11. Epub 2012 Mar 19.

Abstract

6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid β-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In a fluconazole-resistant clinical isolate of C. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alkynes / pharmacology
  • Antifungal Agents / pharmacology*
  • Candida albicans / drug effects
  • Candida albicans / genetics
  • Candida albicans / metabolism
  • Fatty Acids / metabolism*
  • Fatty Acids, Monounsaturated / pharmacology
  • Fatty Acids, Unsaturated / pharmacology
  • Fluconazole / pharmacology
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism

Substances

  • 6-nonadecynoic acid
  • Alkynes
  • Antifungal Agents
  • Fatty Acids
  • Fatty Acids, Monounsaturated
  • Fatty Acids, Unsaturated
  • 2-hexadecynoic acid
  • Fluconazole