Highlights d Bile acid 7a-dehydroxylating gut bacteria secrete tryptophan-derived antibiotics d Secondary bile acid enhanced the activity of these antibiotics d Tryptophan-derived antibiotics appear to inhibit the division septum of bacteria d Clostridium difficile secretes proline-based cyclic dipeptides

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Members of the genera Phellinus and Inonotus, including P. linteus, P. igniarius, P. ribis, I. obliquus and I. xeranticus are well-known medicinal fungi (mushrooms) and have been used in treatment of cancer, diabetes, bacterial and viral infections and ulcer. Adverse effects of these medicinal mushrooms have not yet been reported, indicating the safe nature of these mushrooms. Polysaccharides, particularly b-glucan, are considered the compounds responsible for the biological activity of medicinal mushrooms. However, there is only a limited amount of evidence to indicate that polysaccharides are in fact responsible for the biological effects of these medicinal mushrooms. Recently, many research groups have begun identification of active low-MW compounds in medicinal mushrooms, with a focus on the yellow polyphenol pigments, which are composed of a styrylpyrone class of compounds. Interestingly, a representative group of medicinal fungi, including P. linteus, P. igniarius, P. ribis, I. obliquus and I. xeranticus were shown to produce a large and diverse range of styrylpyrone-type polyphenol pigments that exhibited various biological activities, including anti-oxidative, anti-inflammatory, cytotoxic, anti-platelet aggregation, anti-diabetic, anti-dementia and anti-viral effects. Styrylpyrone pigments in mushrooms are thought to have a role similar to that of flavonoids in plants. The unique and unprecedented carbon skeleton of fused styrylpyrone might be an attractive molecular scaffold for pharmacological applications. In this review, the structural diversity, biological effects and biogenesis of styrylpyrone-class polyphenols from medicinal fungi are described.

Zorbamycin (1, ZBM) is a glycopeptide antitumor antibiotic first reported in 1971. The partial structures of 1 were speculated on the basis of its acid hydrolysis products, but the structure of the intact molecule has never been established. The low titer of 1 from the wild-type strain, combined with its acid-instability, has so far hampered its isolation. By random mutagenesis of Streptomyces flavoviridis ATCC21892, a wild-type producer of 1, with UV irradiation, two high-producing strains of 1, S. flavoviridis SB9000 and SB9001, were isolated. Under the optimized fermentation conditions, these two strains produced about 10 mg/L of 1, which was about 10-fold higher than the wild-type ATCC21892 strain, as estimated by HPLC analysis. Finally, 1 was isolated as both a 1-Cu complex and Cu-free molecule, and the intact structure of 1 was established on the basis of a combination of mass spectrometry and 1H and 13C NMR spectroscopic analyses.

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Microbial metabolites isolated in screening programs for their ability to activate transcription of the tipA promoter (ptipA) in Streptomyces lividans define a class of cyclic thiopeptide antibiotics having dehydroalanine side chains ("tails"). Here we show that such compounds of heterogeneous primary structure (representatives tested: thiostrepton, nosiheptide, berninamycin, promothiocin) are all recognized by TipAS and TipAL, two in-frame translation products of the tipA gene. The Nterminal helix-turn-helix DNA binding motif of TipAL is homologous to the MerR family of transcriptional activators, while the C terminus forms a novel ligand-binding domain. ptipA inducers formed irreversible complexes in vitro and in vivo (presumably covalent) with TipAS by reacting with the second of the two C-terminal cysteine residues. Promothiocin and thiostrepton derivatives in which the dehydroalanine side chains were removed lost the ability to modify TipAS. They were able to induce expression of ptipA as well as the tipA gene, although with reduced activity. Thus, TipA required the thiopeptide ring structure for recognition, while the tail served either as a dispensable part of the recognition domain and/or locked thiopeptides onto TipA proteins, thus leading to an irreversible transcriptional activation. Construction and analysis of a disruption mutant showed that tipA was autogenously regulated and conferred thiopeptide resistance. Thiostrepton induced the synthesis of other proteins, some of which did not require tipA.Directed searches for microbial secondary metabolites that inhibit bacterial growth led to the discovery of antibiotics and thus gave rise to the traditional interpretation that their only biological relevance is to inhibit growth of competing organisms. Nevertheless, antibiotics often have alternative molecular targets and, like other secondary metabolites, elicit numerous "unexpected" effects on microbial differentiation (1-4) and mammalian cell function (1). Here we describe how a single transcriptional activator can interact with diverse thiopeptide antibiotics to elicit autogenous expression of its own promoter as well as a modulon in Streptomyces lividans (SL). 1Thiopeptides are a family of antibiotics composed of a ring structure containing highly modified amino acids and a linear peptide containing dehydroalanines extending from the ring at a pyridyl group ("tail") ( Fig. 1). They were first discovered as antibiotics synthesized by diverse bacteria including Streptomyces, Bacillus, and Micrococcus. These compounds later proved to be effective growth promotants for domestic animals (2-4), an effect whose biological basis is not clear. Thiostrepton, whose antibiotic activity is best understood, acts by binding tightly to the procaryotic ribosome and thus inhibiting translation (5-8). In a thiostrepton-producing organism, Streptomyces azureus, methylation of a specific nucleotide in the 23 S rRNA can provide resistance. Such methylated ribosomes do not bind and are therefore not sensitive to thiostrep...

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A total of 62 bacterial isolates were obtained from Gomsohang mud flat, Mohang mud flat, and Jeju Island, Republic of Korea. Among them, the isolate CNU114001 showed significant antagonistic activity against pathogenic fungi by dual culture method. The isolate CNU114001 was identified as Bacillus amyloliquefaciens by morphological observation and molecular data analysis, including 16SrDNA and gyraseA (gyrA) gene sequences. Antifungal substances of the isolate were extracted and purified by silica gel column chromatography, thin layer chromatography, and high performance liquid chromatography. The heat and UV ray stable compound was identified as iturin, a lipopeptide (LP). The isolate CNU114001 showed broad spectrum activity against 12 phytopathogenic fungi by dual culture method. The semi purified compound significantly inhibits the mycelial growth of pathogenic fungi (Alternaria panax, Botrytis cinera, Colletotrichum orbiculare, Penicillium digitatum, Pyricularia grisea and Sclerotinia sclerotiorum) at 200 ppm concentration. Spore germ tube elongation of Botrytis cinerea was inhibited by culture filtrate of the isolate. Crude antifungal substance showed antagonistic activity against cucumber scleotiorum rot in laboratory, and showed antagonistic activity against tomato gray mold, cucumber, and pumpkin powdery mildew in greenhouse condition.