Four tachykinin (NK2) receptor inhibitors, SCH 378161 (1), SCH 217048 (2), SCH 378199 (3), and SCH 378167 (4) were isolated from the fermentation broth of a taxonomically unidentified fungus. These compounds were separated from the fermentation broth by ethyl acetate extraction. Purification and separation of the individual compounds were achieved by NK2 assay-guided fractionation using gel filtration, reverse phase chromatography and HPLC. They were identified to be a family of depsipeptides by spectroscopic and degradation studies. Compounds 1 and 3 contain proline and differ as an amide and acid whereas 2 and 4 contain pipecolic acid and differ in being an amide and acid. All of these compounds contain an identical hydroxy acid. They are selective NK2 inhibitors with Ki values ranging from 27-982 nM and demonstrate no activity at 10 μM in the NK1 and NK3 assays. In addition, compounds 1 and 2 inhibited NKA-induced increases in the concentration of intracellular Ca2+, [Ca2+]j, in a CHO cell expressing the human NK2 receptor; this inhibition was competitive in nature with pA2 values of 7.2 and 7.5, respectively. These data demonstrate that these natural products are selective and competitive receptor antagonists of the human NK2 receptor.
A novel anti-influenza agent, FR198248, was isolated from the cultured broth of a fungal strain No. 13830. The strain was identified as Aspergillus terreus from morphological characteristics. FR198248, a new type of hydroxyl benzaldehyde compound, showed anti-influenza virus activity in Madin-Darby canine kidney (MDCK) cells in vitro. The mode of action of FR198248 against influenza virus A could be ascribed to an inhibitory effect on the stage of virus adsorption. Furthermore, FR198248 possessed potent in vivo anti-influenza activity in a murine model of respiratory tract infection.
Nonproducer mutants support the assumption that epothilones A and B are synthesized by the same polyketide synthase (PKS). The endproducts of the PKS, epothilones C and D, compete for the active site of a constitutively synthesized monooxygenase which is regulated by product inhibition. The postulated C-13 hydroxy-epothilones as direct precursors of epothilones C and D were not detected.
Haliangicin, a novel β-methoxyacrylate antibiotic with a conjugated tetraene moiety, was isolated from the culture broth of a marine myxobacterium. A bacterium tentatively named as Haliangium luteum required 2-3% NaCl for the growth and production of haliangicin. Haliangicin inhibits the growth of a wide spectrum of fungi but was inactive against bacteria. In mitochondrial respiratory chains, haliangicin interfered the electron flow within the cytochrome b-c1 segment.
A novel antifimgal antibiotic, haliangicin, was isolated from a culture broth of marine myxobacterium, Haliangium luteum. The planar structure of haliangicin was elucidated by spectroscopic analyses and was shown to be a new polyunsaturated compound containing β-methoxyacrylate moiety.
Studies on the susceptibility of pathogenic Nocardia to macrolide antibiotics, chalcomycin and tylosin, showed that most of the Nocardia species examined were highly resistant to both antibiotics, although N. nova was moderately susceptible. N. asteroides IFM 0339 converted these macrolides into inactive metabolites by glycosylation at 2'-OH or glycosylation and reduction of the 20-formyl group. The structures of the metabolites were determined from NMR and MS data to be 2'-[O-(β-D-glucopyranosyl)]chalcomycin (2), 2'-[O-(β-D-glucopyranosyl)]tylosin (5) and 20-dihydro-2'-[O-(β-D-glucopyranosyl)]tylosin (4).
Pseudomonic acid A (1) has been the dominant commercial pseudomonate antibiotic produced by Pseudomonas fluorescens. In specific shaken flask conditions initial fermentation accumulation of 1 is followed by preferential accumulation of the 8-hydroxy derivative, pseudomonic acid B (2). Biosynthetic probing with a pulse of [1-14C] acetate or L-[methyl-14C] methionine at early, mid and late stages of the fermentation gave relative patterns of radioactivity in 1 and 2 that are inconsistent with an assumption that 2 arises by oxidation of 1, or that 1 is formed by reduction of 2. Since [methyl-14C] methionine only labels carbons in the 12-carbon part of the pseudomonate molecule that is thought to be an early biosynthetic moiety, the evidence from radiolabelling experiments implies that preferential early oxidation of this biosynthetic intermediate causes the pathway diversion to accumulate 2 instead of 1.