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

Abstract

c 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 ␤-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.

Plant-Derived Antimicrobial Compounds: Alternatives to Antibiotics

“…Moreover, metronidazole showed a potentiation of its antifungal effect when combined with plant extracts [122,123], as did fluconazole with other phytocomponents [114]. Using genetic and biochemical approaches, Xu et al showed the antifungal activity of a plant-derived acetylenic acid by interfering with the fatty acid homeostasis pathway [124].…”

Antibacterial activity of 2-alkynoic fatty acids against multidrug-resistant bacteria

“…Acetylenic fatty acids have been widely studied by medicinal chemists due to their interesting antimicrobial properties such as antifungal (Carballeira, 2008; Carballeira et al, 2006; Carballeira et al, 2005; Gershon and Shanks, 1978; Li et al, 2003; Li et al, 2008; Xu et al, 2012), antiprotozoal (Carballeira et al, 2012; Tasdemir et al, 2010), and antibacterial activities (Konthikamee et al, 1982; Morbidoni et al, 2006). Acetylenic fatty acids are mainly produced by certain plants as a chemical defense against microorganisms (Cahoon et al, 2003; Carballeira, 2008; Fatope et al, 2000; Li et al, 2003; Li et al, 2008; Xu et al, 2012). Among the acetylenic fatty acids, the 2-hexadecynoic acid (2-HDA) has received the most attention for its antimicrobial and cytotoxic properties (Carballeira et al, 2012; Carballeira et al, 2006; Gershon and Shanks, 1978; Morbidoni et al, 2006; Upreti et al, 1981; Wood and Lee, 1981).…”

Protocol for Identifying Natural Agents That Selectively Affect Adhesion, Thickness, Architecture, Cellular Phenotypes, Extracellular Matrix, and Human White Blood Cell Impenetrability of Candida albicans Biofilms

“…The power of the protocol is that all nine parameters are obtained from a single z-stack of CLSM scans of an individual biofilm preparation rather than from separate preparations in separate experiments. We first assessed the effectiveness of this protocol on five crude extracts and extract-derived compounds previously demonstrated to inhibit the growth of C. albicans in suspension or on a plastic surface (54)(55)(56)(57)(58)(59)(60)(61)(62). All five extracts and all five extract-derived antifungal agents caused aberrant biofilm formation, on the basis of a comparison with the phenotypic profiles afforded by the nine parameters of the untreated control preparations, but the profiles differed between extracts in some cases and between the extract and the extractderived agent in two cases.…”