In our survey for antifungal compounds, a fermentation broth of Streptomyces sp. HA81-2 was found to inhibit the in vitro growth of Aspergillus fumigatus IFO 5840 accompanied by hyphal morphological abnormalities. One of the isolated antibiotics was identified as phoslactomycin E based on LC-MS and NMR spectral data. In a preliminary assay using the membrane fractions of A. fumigatus, phoslactomycin E was found to inhibit the activity of 1,3-b glucan synthase.Keywords antifungal activity, phoslactomycin E, Aspergillus fumigatus, hyphal morphological abnormalities, 1,3-b glucan synthase Opportunistic fungal infections are a major cause of serious morbidity and mortality in immunocompromised patients. However, there are few drugs for antifungal chemotherapy of deep-seated mycosis. As both human and fungal cells are eukaryotes, it is difficult to develop antifungal drugs without side effects in human hosts. Current targets are limited to ergosterol, cell wall components, biosynthetic pathways of cell wall and cytosine deaminase [1,2]. Therefore, there is a great need for novel antifungal drugs with new mechanisms of action. Morphological deformation of fungal hyphae is often induced by antifungal drugs [3]. As this phenomenon is specific to fungi, it could be used to screen for selective antifungal antibiotics [4]. In addition, this hyphal deformation is expected to reflect the disruption of cell wall biosynthesis, which is a specific target of antifungal agents. Moreover, investigating the mechanism of antifungal-induced hyphal morphological abnormalities is potentially useful for understanding the morphogenesis of fungal hyphae.In the course of our search for antifungal antibiotics, we found that a fermentation broth of Streptomyces sp. HA81-2 exhibited antifungal activity against Aspergillus fumigatus IFO 5840 accompanied by hyphal abnormalities. The isolated active fraction was identified as phoslactomycin E (PLME) [5] based on LC-MS and NMR spectral data. We herein report the isolation procedures for PLME, its molecular characteristics, and its induction of morphological changes in fungal cells.Active principles were isolated as follows; fermentation broth was filtered, the filtrate was applied on Diaion HP-20 column, and then eluted using an increasing gradient of aq MeOH (10ϳ100%). The 80ϳ90% MeOH fractions were concentrated in vacuo to afford crude extract, which was partitioned between water and CHCl 3 . Purification of
Significance and Impact of the Study: Combination therapies that utilize adjuvant antibiotic and nonantibiotic drugs to potentiate antibiotic activity are emerging as an attractive approach to counteract fungal resistance to drugs. In this study, we investigated the structure-activity relationships of phenylpropanoids and related derivatives that restrict drug resistance by inhibiting their efflux. A desirable synergy was observed when n-dodecanol or fluconazole was combined with a phenylpropanoid anethole and p-alkylanisoles having alkyl chains with a length of C2-C6. Our results provide a foundation for the practical application of combination therapies against antifungal resistance.
Pterostilbene has been shown to exhibit antifungal activities. However, the detailed action mechanism is unknown. Here, we analyzed the antifungal mechanism of pterostilbene against Saccharomyces cerevisiae. The minimum growth inhibitory and fungicidal concentrations of pterostilbene were 120 and 240 µM in a YPD medium, respectively. Although pterostilbene produced reactive oxygen species (ROS), resveratrol did not. This effect was maximized at 120 µM. Furthermore, α-tocopherol acetate inhibited ROS production and reversed pterostilbene-induced growth inhibition. At 240 µM, pterostilbene showed fungicidal effects accompanied by the leakage of intracellular potassium ions, suggesting the involvement of membrane injury in addition to oxidative stress in fungicidal action. Nevertheless, the antioxidants gradually reversed the decrease in cell viability caused by pterostilbene, suggesting that ROS production mainly contributed to the lethal effect. As Pterocarpus marsupium extract, mainly containing pterostilbene, is used as a traditional medicine, pterostilbene has great potential for development as a preservative with fewer adverse effects.
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