Contragestational profile of the tumor-inhibiting agent, L-alanosine, in the rat and the hamster.

L-Alanosine [L-2-amino-3(N-hydroxy-N-nitrosamino)propionic acid], a tumor-inhibiting agent, induces pregnancy arrest after single or multiple SC or PO administration to rats and hamsters. Its contragestational effects are dose- and route-dependent, with no important differences in species-sensitivity or administration schedules. L-Alanosine is maximally effective shortly (3-4 days) after implantation. Both placenta and fetus appear to be target tissues. Consistent with previous in vitro findings, adenine but not aspartic acid counteracts the contragestational action of L-alanosine. The 'contragestational test', i.e., the effect on conceptus growth, appears to be an interesting approach for learning more about the antiproliferative activity of an antineoplastic agent.

On the mode of action of a new contragestational agent (DL 111-IT).

Non-hormonal compounds belonging to 3,5-diphenyl-1H,1,2,4 triazoles and chemically related classes (triazoles in short) are known to be endowed with high contragestational activity in rodents, dogs and primates. The data herein reported for one of the leaders of this family of compounds (DL 111-IT) along with those previously reported for some analogues, demonstrate that triazoles cause pregnancy arrest by a direct action on conception product. This action is expressed through a progressive slowing down of the conceptus development with a consequent onset of a state of anoxia, pregnancy arrest, degeneration of placentae and adnexae and their absorption or expulsion. The selective time of gestation during which they elicit the antifertility effect (early post-implantation period) and the histological examinations revealed that the target of their action are the ectoplacental and decidual cells. Biochemical studies on conceptus product demonstrate that, although they do not bind to progesterone receptors or inhibit ornithine decarboxylase activity, triazoles induce an early and marked increase in the number of cytosol progesterone receptors accompanied by a steep decrease in the ornithine decarboxylase activity in the product of conception. These findings are discussed in relation to the possibility that triazoles may trigger pregnancy arrest by interfering with the chain of events by which progesterone regulates the mitotic activity of decidual and trophoblastic cells.

Gardimycin, a new antibiotic from Actinoplanes. II. Isolation and preliminary characterization.

The strain Actinoplanes garbadinensis nov. sp. produces a peptide antibiotic, named gardimycin, which is active in vitro and in vivo against Gram-positive bacteria. Isolation and purification of the product have been accomplished by extraction from the broth with butanol and dialysis of the crude extract, followed by counter-current distribution. Gardimycin is an open chain peptide with an approximate minimal formula C84H138N18S3-4O34Na. The following amino acids have been identified by column chromatography of an acid hydrolysate: serine, glutamic acid, alanine, leucine, isoleucine, glycine, valine and two sulphur-containing amino acids whose structure is presently under study. Tryptophan has been identified in an alkaline hydrolysate.

Lipiarmycin, a new antibiotic from Actinoplanes. II. Isolation, chemical, biological and biochemical characterization.

Lipiarmycin, a metabolite of Actinoplanes deccanensis nov. sp. (PARENTI et al.), has been isolated in pure form. It has a molecular formula C52 CONGRUENT TO 54H74 CONGRUENT TO 76Cl2O19, (M.W. = 1,073 CONGRUENT TO 1,099). From its chemical and physico-chemical characteristics, lipiarmycin can be considered a new antibiotic. Lipiarmycin is highly active against Gram-positive bacteria, including strains resistant to the medically important antibiotics and protects mice experimentally infected with Streptococcus haemolyticus. Liparmycin inhibits growth of susceptible bacteria by interfering with RNA synthesis.

Microbial de-mannosylation and mannosylation of teicoplanin derivatives.

The single components of the teicoplanin complex, glycopeptide antibiotics active against Gram-positive bacteria, can be converted in the corresponding de-mannosyl derivatives by cultures of Nocardia orientalis NRRL 2450 or Streptomyces candidus NRRL 3218. Conversely, teicoplanin aglycone and other teicoplanin de-mannosyl derivatives can be converted in the corresponding teicoplanin mannosyl derivatives by cultures of Actinoplanes teichomyceticus ATCC 31121. The biological transformation yields are approximately 40% for de-mannosylation and 90% for mannosylation. The processes allow for the preparation of gram quantities of the de-mannosyl derivatives of teicoplanin and of teicoplanin mannosyl derivatives. De-mannosyl teicoplanin and teicoplanin mannosyl-pseudoaglycone were not amenable to preparation by either acidic or basic chemical hydrolysis.

Isolation and structure determination of two new analogs of teicoplanin, a glycopeptide antibiotic.

Teicoplanin is an antibiotic produced by fermentation of Actinoplanes teichomyceticus as a complex formed by five closely related glycopeptides characterized by different fatty acid chains of ten and eleven carbon atoms. In addition, minor quantities of related substances are present. Two of them, named RS-1 and RS-2, were shown to be teicoplanins having as fatty acid chains 10-methylundecanoic acid and n-dodecanoic acid, respectively. Other two related substances, named RS-3 and RS-4, have now been isolated and purified starting from fermentation broths of a mutant of the same microorganism producing them in substantial amounts. This was achieved by semipreparative reversed-phase liquid chromatography carried out on high-pressure scale. The structures were assigned on the basis of 1H NMR spectra and homonuclear COSY 2D experiments and fast atom bombardment MS spectrometry, in comparison with the large mass of data till now accumulated on teicoplanin. RS-3 and RS-4 are teicoplanins having as fatty acid chains 6-methyloctanoic acid and n-nonanoic acid, respectively.

Isolation and structure determination of a novel complex of the teicoplanin family.

A new teicoplanin-like antibiotic was discovered when using Actinoplanes teichomyceticus strain 3/W, the fermentation medium containing Alburex, and the fermentation time 275 hours. The new product was separated from teicoplanin complex by polyamide resin chromatography and purified by Amberlite XAD-7 and affinity resin chromatographies. The structure was established on the basis of the physico-chemical characteristics of the complex and of its aglycone. The new structure is that of teicoplanin with a carbonyl group substituting for the CHNH2 group of amino acid 1. We hypothesize that the novel complex is a transformation product of teicoplanin due to a simple transamination reaction, as supported by its structure and by the concomitant decrease in teicoplanin concentration during its production.

Mechanism of action of rifampin on Mycobacterium smegmatis.

Deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase (EC 2.7.7.6) isolated from a rifampin-sensitive strain of Mycobacterium smegmatis was 90% inhibited by 1 mug of rifampin per ml; enzyme from a rifampin-resistant mutant was not affected by this concentration of antibiotic. Inhibition of phenylalanine-1-(14)C incorporation by rifampin in growing cultures was complete about 6 min after addition of antibiotic. Under the same conditions, uracil-2-(14)c incorporated was blocked after 1.5 to 2 min. Rifampin kills M. smegmatis very slowly. When rifampin-inhibited cultures were transferred to a rifampin-free medium, there was a partial resumption of uracil-2-(14)C incorporation, even in the presence of chloramphenicol. We conclude that a primary event in the inhibition of M. smegmatis by rifampin is the block of DNA-dependent RNA polymerase.

1-Methyl-2-nitroimidazol-5-yl derivatives. IVth Communication.

The chemico-physical data and antimicrobial activities are described of a new series of 2-nitroimidazole derivatives prepared by condensing 1-methyl-2-nitroimidazole-5-carboxaldehyde with N-substituted hydroxylamines, N-aminopiperazines and N-aminopiperidines.

Factors affecting the normal and branched-chain acyl moieties of teicoplanin components produced by Actinoplanes teichomyceticus.

Teicoplanin, a glycopeptide antibiotic produced by Actinoplanes teichomyceticus, comprises five main components, denoted T-A2-1 to T-A2-5, differing in the structure of their acyl side chain, which is linear in T-A2-1 and T-A2-3 and branched in the other components. Production of T-A2-1, characterized by a linear C10:1 acyl moiety, is entirely dependent on the presence of linoleate in the fermentation medium. Addition to the medium of oleic acid esters at 2 g l-1 increases the yields of T-A2-3, characterized by a linear C10:0 acyl chain, about threefold. The antibiotic linear side chains thus appear to originate from C18 unsaturated acid by beta-oxidation degradation. The percentage of T-A2-2, T-A2-4 and T-A2-5, bearing the iso-C10:0, anteiso-C11:0 and iso-C11:0 acyl moieties, respectively, is strongly influenced by the presence in the medium of the amino acids known to be precursors of branched-chain fatty acids. Thus, valine increases the production of T-A2-2 whereas isoleucine or leucine increase the relative yields of T-A2-4 or T-A2-5, respectively. Analysis of the total cell lipids upon addition of the same amino acid shows corresponding increases in the proportion of the iso-C16:0, iso-C15:0 or anteiso-C17:0. A mutant A. teichomyceticus strain, which produces a novel teicoplanin with a linear C9:0 chain, differs from the wild strain in the presence of the linear C17:1 acid in its lipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the acyl moieties of the antibiotic complex A40926 and their relation with the membrane lipids of the producer strain.

Structures of the fatty acid residues characterizing the various components of A40926 were determined by gas chromatography/mass spectrometry on the methyl esters obtained by methanolysis of the complex. The results confirm the residues previously assigned to Factor A (n-undecanoic acid) and B (10-methyl-undecanoic acid) and establish the residues of Factor A1 (9-methyl-decanoic acid), B1 (n-dodecanoic acid), RS1 (8-methyl-nonanoic acid), RS2 (n-decanoic acid), and RS3 (n-tridecanoic acid). As the Actinomadura species contain in their mycelia large quantities of C15-C17 fatty acid residues as membrane phospholipids, these mycelia were saponified and the fatty acids obtained were analyzed as above. There is a close correlation between the fatty acid content of A40926 complex and that of the longer homologues in the producer mycelia.