Tetronomycin, C34H50O8, isolated from a strain of Streptomyces sp. nov. represents a novel polycyclic ionophore polyether. The crystal structure and absolute configuration were established by X-ray analysis of the mono-O-acetyltetronomycin silver salt. Tetronomycin is the first metabolic polyether which contains a tetronic acid moiety instead of the essential carboxylic acid function. A trisubstituted cyclohexane ring and an interesting molecular conformation of the silver salt represent additional unique structural features. Extensive NMR-studies enabled the assignment of chemical shifts and the correlation of the proton and carbon signals. Tetronomycin exhibits activity against Gram-positive bacteria.
New vasodilators, designated WS-1228 A and B have been discovered in the culture filtrate of a strain of Streptomyces aureofaciens. The active compounds were purified by column chromatography with Diaion HP-20 and silica gel, and finally separated from each other by high performance liquid chromatography. They were obtained as pale yellow crystals and their molecular formulae were both C11H17N3O.
The structure of new hypotensive vasodilators, WS-1228 A and B, produced by Streptomyces aureofaciens, were determined as 1 and 2, respectively, on the basis of their spectral and chemical evidences. WS-1228 A (1), having N-hydroxytriazene moiety, was synthesized from (E, E, E)-2, 4, 7-undecatrienal (4) by condensation with hydrazine hydrate followed by nitrosation.
Auramycins A and B and sulfurmycins A and B, new anthracycline antibiotics were discovered from the culture of a strain OBB-111, which was identified as Streptomyces galilaeus. The structures of the antibiotics were determined, indicating that auramycins and sulfurmycins are anthracycline glycosides of new aglycones designated auramycinone and sulfurmycinone.
The new anthracyclines 4-O-demethyl-11-deoxydoxorubicin, 4-O-demethyl-11-deoxydaunorubicin along with its 13-dihydro and 13-deoxo analogues are the main components of the anthracycline complex produced by cultures of Streptomyces peucetius var. aureus. They were isolated by solvent partition, separated by column chromatography and characterized by chemical and physical methods. Among these new anthracyclines, displaying antibacterial and cytotoxic activity "in vitro", 4-O-demethyl-11-deoxydoxorubicin and the corresponding daunorubicin analogue were also active against experimental tumors.
Strains of Chromobacterium: violaceum, isolated from various environments, were found to produce a novel monocyclic β-lactam antibiotic. The antibiotic, SQ 26, 180 was weakly active against Gram-positive and Gram-negative bacteria with the exception of mutants hypersensitive to β-lactam antibiotics. The compound was highly stable to β-lactamases and acted as an inhibitor of the P99 enzyme from Enterobacter cloacae. SQ 26, 180 showed affinity for penicillin-binding proteins la, 4 and 5/6 of Escherichia coli and inhibited R61 DD-carboxypeptidase.
A novel monocyclic β-lactam antibiotic SQ 26, 180 has been isolated from bacteria and the structure, (R)-3-acetylamino-3-methoxy-2-oxo-1-azetidinesulfonic acid was deduced from its spectroscopic properties. Structural confirmation and assignment of absolute configuration were made by synthesis from 6-aminopenicillanic acid.
25-Dihydrosaframycin A(AR1) and 21-decyano-25-dihydrosaframycin A(AR3) were produced by the microbial conversion of saframycin A(SA). Efficient conversion of SA to AR1 and AR3 was observed with Rhodococcus amidophilus IFM 144. Though the antimicrobial activity of AR1 was one tenth that of SA, the in vitro antitumor activity of AR1 was found to be equivalent to that of SA. In contrast, AR3 was biologically less active.
Aculeacin A is a cyclopeptide-containing long-chain fatty acid, representing a new class of antibiotics. It has a relatively narrow antifungal spectrum in vitro and is highly active against some groups of yeasts. Of 31 strains of Candida and Torulopsis tested, the majority were susceptible to aculeacin A at 0.31μg per ml or less. On the other hand, the antibiotic was scarcely active or inactive against other yeasts, such as Cryptococcus neoformans, and all filamentous and dimorphic fungi tested. A distinct inoculum effect has been observed in vitro with a number of strains of C. albicans; minimum growth-inhibitory concentrations (MIC) have tended to increase with increased incubation time. MIC values were also increased in the presence of serum. Aculeacin A is fungicidal for growing cells of C. albicans. It was most lethal against sensitive yeasts at 0.08 to 0.31μg per ml, and increases in the concentration of the drug above this range reduced, rather than increased, its lethal effect.
Aculeacin A was lethal for proliferating cultures of C. albicans. However, there was a paradoxical relationship between the drug concentration and the fungicidal activity; the lethal effect was the greatest at levels of 0.08 to 1.25μg/ml and increases in the drug concentration above this range reduced its lethal effect. A similar anomalous dose-response patterns were also observed for the inhibitory effect of the drug on several cellular and subcellular biochemical activities. Association of this lethal effect of the drug was the formation of visible cell aggregates and the development of extremely huge forms in treated cultures. Aculeacin A induced osmotically fragile cells and viability of treated cultures was markedly reversed under high osmolarity. Tracer experiments and chemical analysis revealed that synthesis of alkali-insoluble glucan was inhibited by the drug to a greater extent than synthesis of mannan and any other species of macromolecules, with resultant formation of alkali-insoluble glucan-deficient cells. Aculeacin A inhibited synthesis of β-glucan from UDP-glucose catalyzed by cell-free extracts from C. albicans and S. cerevisiae. These data are consistent with the view that one of the principal target of aculeacin A action is on the, β-1, 3-glucan synthetase reaction.
A series of aliphatic amides of amphotericin B have been synthesized. The structure of the derivatives which were obtained has been established by mass spectrometry. Their biological properties: inhibition of growth of Saccharomyces cerevisiae and hemolytic activity have been determined. The quantitative relationships between the activity of amides of amphotericin B against S. cerevisiae and their lipophilicity can be expressed by a parabolic function, whereas that between hemolytic activity and lipophilicity-by polynominal expression of fourth degree.
The antifungal effect of a polyene antibiotic amphotericin B (AMB) was almost completely abrogated by exogenous addition of 0.1μg/ml ergosterol in the medium. The cytocidal effect of AMB on Saccharomyces cerevisiae was synergistically enhanced when cultured for more than 4 hours with squalene, an obligatory intermediate molecule for sterol formation. However, we could not find significant increase in cellular level of ergosterol content in the yeast cells fed with squalene.
A broad host range multiresistance plasmid pPK237, originating from Pseudomonas aeruginosa mediates high-level resistance to gentamicin and tobramycin. It was found to code for two gentamicin modifying enzymes, which from their substrate profile by radioenzymatic assay were characterized as aminoglycoside acetyltransferase AAC(3)-I and aminoglycoside adenylyltransferase AAD(2"). The two enzymes were studied after purification from an Escherichia coli K12 host. The two gentamicin-modifying enzymes coded by pPK237 were completely separated by DEAE chromatography. The purification (126 fold) of the acetyltransferase was achieved by (NH4)2SO4 precipitation, DEAE chromatography and affinity chromatography. The purification of the adenylyltransferase was performed by affinity chromatography directly after (NH4)2SO4 precipitation. Both purified enzyme preparations showed a single protein band on disc electrophoresis. The Km for gentamicin C1 of the acetyltransferase was 0.066 mM. The amino acid analysis of the acetyltransferase coded by pPK237 showed a different aminoacid composition than that of the gentamicin acetyltransferase AAC(3)-I purified by WILLIAMS and NORTHROP17). The acetyltransferase after DEAE chromatography is stable for many months at -20°C, while the adenylyltransferase after purification is highly unstable; it shows enzymatic activity only in the presence of Mg++.