In a search for new inhibitors of the TNF-α promoter activity, a new spiro-compound, designated oxaspirodion, was obtained as a mixture of four isomers from fermentations of the ascomycete Chaetomium subspirale. The structure was determined by a combination of spectroscopic techniques.
Laschiatrion (1), a new antifungal antibiotic, was isolated from fermentations of Favolaschia sp. 87129. (1) exhibits broad in vitro activity against several human pathogens while no antibacterial and cytotoxic activities could be detected. The structure was elucidated by spectroscopic techniques. As to our knowledge laschiatrion possesses a new steroid skeleton.
In the course of DNA-fingerprinting our strain collection for antibiotic biosynthesis genes, two different type II polyketide synthase (PKS) gene clusters were observed from Streptomyces sp. PGA64. Phylogenetic analysis placed these together with known rubromycin and angucycline biosynthetic gene clusters. The host strain itself has a very clean production profile of secondary metabolites, which composes mainly of rubromycin β under typical fermentation conditions. Sequencing of a 16.5kb fragment from the putative angucycline cluster revealed eight genes that were homologous to typical type II PKS genes responsible for synthesizing aromatic polyketides. These genes were especially similar to genes from known angucycline biosynthetic gene clusters and also synteny to these clusters was observed. In addition, three genes were recognized that are needed for priming the minimal PKS complex before polyketide synthesis can initiate, but which are not normally found to cluster with antibiotic biosynthesis genes. A putative repressor gene that was dissimilar to repressor genes found from well-characterized antibiotic biosynthesis gene clusters was also discovered. Gene disruption of the repressor resulted in partial activation of the cluster and production of two angucycline metabolites, UWM6 and rabelomycin. The results confirm that the DNA-fingerprinting method we have developed can be used to correctly detect compounds that are not visible in chemical screens.
UK-2A is a potent antifungal antibiotic and its structure is highly similar to that of antimycin A3 (AA). UK-2A and AA inhibit mitochondrial electron transport at complex III. C9-UK-2A, which has been prepared to improve the duration of the antifungal activity of UK-2A, shows durable fungicidal activities against various species of fungi and induces both membrane injury and the generation of cellular reactive oxygen species (ROS) against Rhodotorula mucilaginosa IFO 0001 cells. We found that C9-UK-2A inhibited the vegetative growth of Saccharomyces cerevisiae IFO 0203 cells accompanying cellular ROS generation in Sabouraud dextrose (SD) medium, which contained a fermentable carbon source. The ROS generation was completely restricted by pretreatment with a lipophilic antioxidant α-tocopherol. In addition, the pretreatment with the antioxidant protected against the growth inhibition induced by C9-UK-2A. C9-UK-2A also induced ROS generation in isolated mitochondria of the S. cerevisiae cells. The addition of both a complex I inhibitor rotenone and a complex II inhibitor thenoyltrifluoroacetone reduced ROS generation induced by C9-UK-2A in the whole cells and the isolated mitochondria. The addition of the inhibitors of complex III, AA or myxothiazol, or of complex IV, KCN, did not reduce ROS generation. These results suggest that C9-UK-2A induces ROS generation due to the blockade of electron flow at complex III, thereby inhibiting the growth of S. cerevisiae in SD medium.
The in vitro and in vivo antibacterial activities of tricyclic ketolides (TKs: TE-802, TE-806, TE-935, TE-943) have been compared with those of clarithromycin (CAM), azithromycin (AZM) and rokitamycin (RKM). TKs were active against not only erythromycin (EM)-susceptible organisms; aerobic Gram-positive bacteria, some Gramnegative bacteria, anaerobic bacteria and Mycoplasma pneumoniae, but also EM-resistant Staphylococcus aureus (inducible macrolide-resistant strains) as well as EM-resistant Streptococcus pneumoniae (efflux-resistant strains). The therapeutic efficacies of TKs against systemic infections and respiratory tract infection (RTI) caused by Gram-positive bacteria in mice are superior to those of CAM and AZM. The peak plasma levels (Cmax, po) of TE-802 in mice were equal to that of CAM, but the plasma area under the concentration-time curve (AUC24 hours) was 4.7 times that for CAM. The plasma Cmax (po) value for TE-802 in monkey was equal to that of CAM, whereas the AUC8 hours value was three-fourths that of CAM. The pharmacokinetics of TE-802 are similar to those of AZM in mice and monkeys, suggesting the potential for once-daily administration in humans.