ABSTRACT
We purified an Erk1/2-activating component in Agaricus blazei and identified it as brefeldin A (BFA). The extract of A. blazei mycelia (ABE) previously showed an estrogenic gene-expression profile and positive effects in patients with cardiovascular symptoms. Here, we demonstrate that BFA has estrogenic activity in reporter gene assays and stimulates an estrogen-receptor pathway revealed by activation of Erk1/2, although BFA had no growth-stimulating activity in breast cancer MCF-7 cells. The presence of estrogenic activity without any explicit growth-stimulating effect is unique to BFA, and such components are termed here "silent estrogens". To test this hypothesis, we examined the target-gene transcription and signaling pathways induced by BFA. Furthermore, BFA was found in the mycelium but not fruiting body of A. blazei, suggesting the potential use of ABE for therapeutics and its supplementary use in traditional medicines and functional foods.
Subject(s)
Agaricus/drug effects , Brefeldin A/pharmacology , Estrogens/pharmacology , MAP Kinase Signaling System/drug effects , Agaricus/chemistry , Base Sequence , Blotting, Western , Chromatography, High Pressure Liquid , DNA Primers , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effectsABSTRACT
Two new antibiotic depsipeptides, unnarmicins C (1) and A (2), were isolated from the fermentation broth of a marine bacterium, Photobacterium sp. strain MBIC06485. The structure of 1 was established by spectroscopic studies and chiral analyses of its chemical degradation/conversion products, and that of 2 by comparing its NMR, MS, and CD data with those of 1. Both compounds selectively inhibited the growth of two strains belonging to the genus Pseudovibrio, one of the most prevalent genera in the marine environments within the class Alphaproteobacteria.
Subject(s)
Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/chemistry , Depsipeptides/biosynthesis , Depsipeptides/chemistry , Photobacterium/metabolism , Anti-Bacterial Agents/pharmacology , Depsipeptides/pharmacology , Fermentation , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Photobacterium/classification , StereoisomerismABSTRACT
Novel inhibitors of fungal ATP-binding cassette transporters were obtained by screening compounds and crude extracts from marine-derived fungi and bacteria using disk diffusion assays of Saccharomyces cerevisiae strains overexpressing a variety of fungal multi-drug efflux pumps. The cyclodepsipeptides unnarmicin A and unnarmicin C were able to sensitize cells overexpressing azole drug pumps ScPdr5p, CaCdr1p, CgCdr1p, and CgPdh1p to sub-MIC concentrations of fluconazole without affecting the growth of CaCdr2p and CaMdr1p overexpressing cells. Unnarmicin A and unnarmicin C were potent inhibitors of rhodamine 6G efflux of CaCdr1p expressing cells with IC50 values of 3.61 and 5.65 microM, respectively. They inhibited the in vitro CaCdr1p ATPase activity at IC50 values of 0.495 and 0.688 microM, respectively. And most importantly, they were able to sensitize azole-resistant Candida albicans clinical isolates to fluconazole. Unnarmicin A and unnarmicin C are candidate efflux pump inhibitors with the potential to be used as adjuvants for antifungal chemotherapy.