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Title: A potential plant-derived antifungal acetylenic acid mediates its activity by interfering with fatty acid homeostasis

Author
item XU, TAO - University Of Mississippi
item TRIPATHI, SIDDHARTH - University Of Mississippi
item FENG, QIN - University Of Mississippi
item LORENZ, MICHAEL - University Of Mississippi
item WRIGHT, MARSHA - University Of Mississippi
item JACOB, MELISSA - University Of Mississippi
item Mask, Melanie
item Baerson, Scott
item LI, XING-CONG - University Of Mississippi
item CLARK, ALICE - University Of Mississippi
item AGARWAL, AMEETA - University Of Mississippi

Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/2/2012
Publication Date: 6/12/2012
Citation: Xu, T., Tripathi, S.K., Feng, Q., Lorenz, M.C., Wright, M.A., Jacob, M.R., Mask, M.M., Baerson, S.R., Li, X., Clark, A.M., Agarwal, A.K. 2012. A potential plant-derived antifungal acetylenic acid mediates its activity by interfering with fatty acid homeostasis. Antimicrobial Agents and Chemotherapy. 56(6):2894-2907.

Interpretive Summary: This article describes studies performed on the antifungal compound 6-Nonadecynoic acid (6-NDA) in order to understand how it inhibits the growth of fungal pathogens. The results described indicate that 6-NDA interferes with the metabolism of fatty acids, which are key components of cellular membranes. The work described in this study lays the foundation for future studies that can pin-point the exact molecular target of 6-NDA in fungal pathogens. This type of work is important for the development of a candidate antifungal compound, and also could lead to the discovery other compounds exhibiting similar biological and chemical properties.

Technical 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 beta-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.