Potent antifungal activity was detected in fermentation extracts of Sporormiella australis and two related components were isolated from solid fermentations using silica gel and high speed countercurrent chromatography. The most active antifungal component, australifungin, contained a unique combination of α-diketone and β-ketoaldehyde functional groups. Australifungin exhibited broad spectrum antifungal activity against human pathogenic fungi with MICs against Candida spp., Cryptococcus neoformans, and Aspergillus spp. between 0.015 and 1.0 μg/ml. Mode of action studies revealed that australifungin interfered with fungal lipid metabolism by specifically inhibiting sphingolipid synthesis at the step converting Sphinganine to ceramide.
Trachyspic acid, a new metabolite that inhibited heparanase, was isolated from the culture broth of Talaromyces trachyspermus SANK 12191. Its structure was deduced from NMR spectral analyses and chemical reactions as a tricarboxylic acid derivative containing a spiroketal. The IC50 value of trachyspic acid against heparanase was 36 μM.
An antibiotic complex, AKD-2, was isolated from the mycelial cake of Streptomyces sp. OCU-42815. The lipophilic substances in this complex were further purified by a recycling HPLC procedure and were designated AKD-2A, C and D. AKD-2B was obtained as a mixture of AKD-2B1 and AKD-2B2. These substances were identified as monoglycerides having branched chain fatty acids and exhibited both antibacterial and antifungal activities.
A new derivative of phenylalanine, phenamide, was discovered from the fermentation broth of an actinomycete identified as a member of the Streptomyces albospinus cluster. Phenamide was purified using successive CIS reverse phase and cation exchange chromatography. Its structure was determined by spectroscopic and chemical methods. Its molecular formula, C14H20N2O3, was determined by HRFAB-MS. Phenamide showed activity against Septoria nodorum, the causal agent of wheat glume blotch.
Antibiotic 07F275 (1), produced by submerged fermentations of fungal culture LL-07F275, was isolated and characterized despite its inherent instability. Its UV spectrum was identical with that of nemo tin, a member of the allenic polyacetylene family, but a molecular weight of 218 daltons indicated a new compound. Structure 1 was determined on the basis of spectroscopic evidence, particularly NMR. Since 1 is a thirteen carbon-containing allenic diyne, it is closely related to mycornycin.
Determination of the mechanism of action of FK506 and cyclosporin A has yielded new molecular targets involved in signal transduction during T cell activation. A common target of FK506 and cyclosporin A is inhibition of activation of the NFAT transcription factor, for which a specific binding region is present in the promoter of the IL-2 gene. A reporter gene assay has been used to screen for agents that interfere with this early step in T cell activation. Simple aromatic compounds that block NFAT-dependent transcription and show in vitro immunosuppressive activity were isolated from the broth and mycelia of two Streptomyces sp. fermentations. The compounds were active at concentrations that were not directly cytotoxic.
We isolated fluvirucin B2 from the culture broth of Streptomyces as an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). It inhibited PI-PLC of A431 cell cytosol with an IC50 of 1.6 μg/ml. Fluvirucin B2 also inhibited PI-PLC in cultured A431 cells, whereas it did not inhibit phosphatidylinositol synthesis and macromolecular synthesis markedly. It also inhibited epidermal growth factor-induced rapid rounding of A431 cells, in which PI turnover is involved.
Spectroscopic data define the structures of three new antibiotics, 4', 5'-dihydro-oligosporon (4), hydroxyoligosporon (5) and 10', H'-epoxy oligosporon (6) from the nematode-trapping fungus Arthrobotrys oligospora, and confirm the structures of the recently reported antibiotics oligosporon (1) and oligosporol B (3). The absolute configuration of the substituted 7-oxabicyclo[4.1.0]hept-3-ene nucleus of these metabolites is determined by circular dichroic spectroscopy. Oligosporon (1) and its dihydro-derivative (4) represent the second and most complex structural type of nematocidal metabolite to be characterised from cultures of nematophagous fungi.
6-α and 6-β Alkylcarbonylmethyl penems were synthesized from 6-α-bromo and 6-oxo penicillanates respectively and their in vitro antibacterial activity was studied. The compounds were generally active against Gram-positive but not against Gram-negative strains, the compounds of the 6-β series being more active. Relatively to imipenem, taken as reference compound, the penems resulted more stable towards chemical hydrolysis in Tris-HCl buffered medium (pH 7.4) but more sensitive towards dehydropeptidase-I (DHP-I).
The neurotoxicity of meropenem was much lower than that of both imipenem and panipenem after intraventricular administration to mice. To clarify the major structural features responsible for the induction of convulsions by carbapenem antibiotics, the structure-activity relationship on convulsant activity was investigated in N-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compounds with strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gamma aminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediated inhibitory transmission. However, the in vivo convulsant activity of some of these compounds did not correlate with their in vitro inhibitory effect on GABAA receptor binding.
(6R, 7R)-7-[2-(2-Amino-4-thiazolyl)-2-[(Z)-[(S)-carboxy(3, 4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(l-methylaminopyridinium-4-thiomethyl)ceph-3-em-4-carboxylate sodium salt (BRL 57342, 1f) combines excellent in vitro antibacterial potency against Gram-positive and Gram-negative bacteria, including P. aeruginosa and Acinetobacter spp., with excellent stability to extended spectrum β-lactamases. This potency is reflected in in vivo efficacy studies.