Metabolic products of microorganisms. 261. Obscurolides, a novel class of phosphodiesterase inhibitors from streptomyces. I. Production, isolation, structural elucidation and biological activity of obscurolides A1 to A4.

A novel class of butyrolactones, named obscurolides, was isolated from the culture filtrate of Streptomyces viridochromogenes by chemical screening methods. The structural elucidation of the obscurolides A1 to A4 (1 approximately 4) is described. The carboxy group of the 4-aminobenzoic acid moiety of obscurolide A1 (1) is reduced in the other compounds. The isolated natural products have been proved to be diastereomeric mixtures by a partial racemization at C-7 which belongs to an allylic alcohol system. The obscurolides showed a weak inhibitory activity against calcium/calmodulin-dependent and independent phosphodiesterases from bovine.

Metabolites of microorganisms. 248. Synthetic analogs of saphenamycin.

A synthesis of racemie saphenic acid is described. From this acid 9 ester derivatives of saphenamycin were prepared. Those with aromatic acid components showed high activity against many Gram-positive and some Gram-negative bacteria. Of the esters with aliphatic acid moieties only the acetate and, to a lesser extent, the butyrate showed considerable anti-bacterial activities, whereas esters with higher fatty acids showed strongly reduced, if any, activities against some test organisms. Similar results were obtained with ID50 values against the eucaryotic tumor cell line CCRF/CEM. The salicylate, which is structurally similar to saphenamycin, was most active.

Metabolites of microorganisms. 247. Phenazines from Streptomyces antibioticus, strain Tü 2706.

From a strain of Streptomyces antibioticus seven yellow phenazines were isolated. The antibacterially most active antibiotic was identified as (-)-saphenamycin, a second one with compound DC-86-Y (saphenic acid). Three compounds were new: Saphenic acid methyl ether, 6-acetylphenazine-1-carboxylic acid and an inseparable mixture of fatty acid esters of saphenic acid. Two simple phenazines were phenazine-1-carboxylic acid (tubermycin B) and unsubstituted phenazine, which was isolated for the first time from a microorganism.

Metabolites of microorganisms. 242 pyridindolol glucosides from Streptomyces parvulus.

From a new strain of Streptomyces, Streptomyces parvulus, strain Tü 2480 three glucosides of the alkaloid pyridindolol were isolated. The structure elucidation is based on spectroscopic investigations and degradation to pyridindolol and alpha,D-methyl glucoside.

Evidence for a common siderophore transport system but different siderophore receptors in Neurospora crassa.

Uptake and competition experiments were performed with Neurospora crassa and Penicillium parvum by using 14C-labeled coprogen and 55Fe-labeled ferrichrome-type siderophores. Several siderophores of the ferrichrome family, such as ferrichrome, ferricrocin, ferrichrysin, and tetraglycyl-ferrichrome as well as the semisynthetic ferricrocin derivatives O-(phenyl-carbamoyl)-ferricrocin and O-(sulfanilyl-carbamoyl)-ferricrocin were taken up by N. crassa. The ferrichrome-type siderophores used vary in the structure of the peptide backbone but possess a common lambda-cis configuration about the iron center and three identical ornithyl-delta-N-acetyl groups as surrounding residues. This suggests that these ferrichrome-type siderophores are recognized by a common ferrichrome receptor. We also concluded that the ferrichrome receptor is lambda-cis specific from the inability to take up the synthetic enantiomers, enantio-ferrichrome and enantio-ferricrocin, possessing a delta-cis configuration about the iron center. On the other hand, we found that coprogen, possessing a delta-absolute configuration and two trans-anhydromevalonic acid residues around the metal center, was also taken up by N. crassa and was competitively inhibited by the ferrichrome-type siderophores. We therefore propose the existence of a common siderophore transport system but the presence of different siderophore receptors in N. crassa. In addition, ferrirubin, which is very slowly transported by N. crassa, inhibited both coprogen and ferrichrome-type siderophore transport. Contrary to the findings with N. crassa, transport experiments with P. parvum revealed the presence of a ferrichrome receptor but the absence of a coprogen receptor; coprogen was neither transported nor did it inhibit the ferrichrome transport.

Metabolites of microorganisms. 229. Absolute configuration of naphthomycin A determined by X-ray analysis and chemical degradation.

The relative and absolute configurations of naphthomycin A were elucidated by an X-ray structural analysis of a methylation product, 25-O-methylnaphthomycin A iminomethyl ether. The absolute configuration was confirmed by degradation (O3, NaBH4) to (S)-butane-1,2,4-triol.

Isolation and structural elucidation of naphthomycins B and C.

Two new ansamycin antibiotics, the naphthomycins B and C, were isolated from two different strains of Streptomyces. The structures were determined by comparison of the spectra (UV, 1H NMR, 13C NMR) with those of the known naphthomycin A, by spin decoupling experiments (300 MHz) and in one case by a two dimensional NMR analysis. Naphthomycin B (II) is 30-chloronaphthomycin C. Strikingly, naphthomycin A (I) differs from B and C not only by the presence of an additional methyl group at C (2), but also in the configuration of some of the double bonds. A fourth ansamycin antibiotic of the naphthomycin subgroup, actamycin, is 30-hydroxynaphthomycin C.

Metabolic products of microorganisms. 200 Isolation and characterization of niphithricins A, B, and elaiophylin, antibiotics produced by Streptomyces violaceoniger.

Fermentations of Streptomyces violaceoniger TU 905 produce the antifungal antibiotics niphithricins A, B, elaiophylin and nigericin. The niphithricins have been characterized as new macrolide antibiotics, and the previously unknown structure of elaiophylin was determined to be a macrodiolide. The niphithricins were biologically active against Gram-positive bacteria and fungi. The mode of action is attributed to an alteration of the membrane permeability.

Biotransformation of lankamycin, darcanolide, and 11-acetyllankolide by a blocked mutant of the erythromcyin producing organism Streptomyces erythreus.

The biotransformation of lankamycin and congeners darcanolide and 11-acetylankolide by a blocked mutant of the erythromycin-producing organism Streptomyces erythreus, which cannot synthesize erythromycin without supplementation with erythromycin precursors, was investigated. Darcanolide and 11-acetyllankolide were converted into the corresponding 15-deoxy-15-oxo derivatives. Lankamycin was transformed to 15-deoxy-15-oxolankamycin, 4''-deacetyl-15-deoxy-15-oxolankamycin and 3'-de-O-methylankamycin. None of the derivatives possessed high antimicrobial activity.

[Metabolic products of microorganisms. 156. Synthesis and biosynthesis of substituted tryptanthrins (author's transl)]. / Stoffwechselprodukte von Mikroorganismen. 156. Mitteilung. Synthese und Biosynthese substituierter Tryptanthrine

Candida lipolytica synthesizes the antibiotic tryptanthrin from 1 mole tryptophan and 1 mole anthranilic acid. When feeding tryptophan and substituted anthranilic acids, or substituted tryptophans and anthranilic acid, we could isolate and identify the expected derivatives of tryptanthrin. The enzymes of the biosynthesis of tryptanthrin, with the exception of bromotryptophan, had no specifity for these substrates. In addition to these experiments substituted tryptanthrines were chemically synthesized. We checked them for antibiotic action; the halogen compounds turned out to be especially effective.

[Metabolic products of microorganisms, 149. Lysolipin I, a new antibiotic from streptomyces violaceoniger (author's transl)]. / Stoffwechselprodukte von Mikroorganismen 149. Mitteilung. Lysolipin I, ein neues Antibioticum aus Streptomyces violaceoniger

From the cultures of Streptomyces violaceoniger, strain Tü 96, two new lipophilic antibiotics, Lysolipin I and Lysolipin X were isolated. The latter one is chemically unstable and is easily transformed to Lysolipin I. The deeply yellow Lysolipin I has a molecular formula C29H24CINO11. It was characterized by the ir, uv, H-nmr and 13C-nmr spectra, which make a quinone structure very probable. Lysolipin I is active against Gram-positive and Gram-negative bacteria. However, enterobacteriae are only inhibited in high dilution, when the membrane permeation is damaged. Lysolipin I acts lytically against bacterial cells. Its activity is decreased by several lipids. The site of action is the biosynthesis of bacterial cell walls, an interaction with the carrier lipid for mureine intermediates being probable.

(S)-3-p-Methoxyphenyl-3-acetylaminopropan-1-ol, a New Metabolite of an Actinomycete.

(S)-3-p-methoxyphenyl-3-acetamidopropan-1-ol was isolated from cultures of an actinomycete (Streptomyces michiganensis). Its structural determination by spectroscopic means and its synthesis are described.