A41030 is a complex of novel glycopeptide antibiotics produced by a culture isolated from a soil. Taxonomic studies have identified the microorganism, NRRL 15156, as a strain of Streptomyces virginiae. The major factor, A41030A, and three of the six minor factors are unique among glycopeptides in that they are naturally occurring aglycones, containing no neutral or amino sugars. The A41030 that was not spontaneously released into the fermentation broth could be released from the biomass into aqueous media at pH 10.5. In contrast to the vancomycin and N-demethylvancomycin fermentations, A41030 biosynthesis was stimulated by enriching the medium with K₂HPO₄ at a level of 1mg/ml. Enrichment with putative precursors of the aglycone, however, did not increase the biosynthesis of A41030.

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Four new dipeptidyl nikkomycins of the Z- and the X-series with a variation in the amino acid moiety of the molecule were isolated from the mutant Streptomyces tendae 901/395 and characterized. Nikkomycins K_z and K_x contain 2-amino-4-hydroxy-4-(2-pyridyl)butyric acid, and nikkomycins O_z and O_x 2-amino-4-hydroxy-4-(5-hydroxy-2-pyridyl)butyric acid. In contrast to nikkomycins Z and X, nikkomycins K_x, and O_x are quite stable at alkaline pH and exhibit a lower biological activity against various test organisms. From the mutant S. tendae 901/C37, which is auxotrophic for methionine and threonine, enhanced amounts of two tripeptidyl nikkomycins, Q_z and Q_x, were produced which are analogues of nikkomycins J and I and contain a homoserine residue instead of glutamic acid. These nikkomycins exhibit a high pH instability.

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Bulgecins A, B and C, new bacterial metabolites which induce the formation of bulges by cooperation with β-lactam antibiotics, were isolated from the culture broth of Pseudomonas mesoacidophila. The three components, separated by column chromatography on QAE-Sephadex A-25, are water-soluble acidic compounds containing a sulfate group in the molecule. Acid hydrolysis showed that D-glucosamine and a new proline derivative are common constituents of the three components. In addition, taurine and β-alanine are constituents of bulgecins A and B, respectively.

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Fast atom bombardment (FAB) mass and MS/MS spectra of a novel quinone antibiotic are presented. Their interpretation is based upon the examination of reductive behavior of model quinones in FAB solvents.

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Acid hydrolysis of vanoxonin yielded one mol each of 2, 3-dihydroxybenzoic acid, L-threonine, L-N^ω-hydroxyornithine. Presence of acetyl group in vanoxonin was suggested by the ¹H NMR. Periodate oxidation of vanoxonin liberated one mol of acetic acid suggesting that the acetyl group bound to the ω-nitrogen of N^ω-hydroxyornithine. The sequence of three components was determined to be L-N-(2, 3-dihydroxybenzoyl)threonyl-L-(N^ω-acetyl-N^ω-hydroxy)ornithine by mass spectrometric analysis. This structure was confirmed by the total synthesis of vanoxonin.

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Quinquevalent vanadium complex with two mol of vanoxonin ligated by the two catechols was shown to be the active structure for inhibition of thymidylate synthetase. The catechol group of vanoxonin as the essential moiety for the inhibition of enzyme was further confirmed by studies of structure-activity relationships using the enzyme obtained from Ehrlich ascites carcinoma cells of mice. Vanoxonin-vanadium complex showed competitive inhibition with respect to deoxyuridylic acid but uncompetitive to 5, 10-methylenetetrahydrofolate.

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The glycopeptide antibiotic vancomycin is unstable in solution. It undergoes a rearrangement involving the conversion of an asparagine residue to isoaspartate to give an antibiotically inactive species, CDP-I. Peptide analogs of bacterial peptidoglycan, such as Ac-D-Ala-D-Ala and di-Ac-L-Lys-D-Ala-D-Ala bind to vancomycin and stabilize the antibiotic against degradation and consequent loss of activity. Protection by peptide is effective even under prolonged heating at 80°C or steam sterilization (30 minutes, 10⁴kg/m²).

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A novel antibiotic was found after performing an interspecific fusion treatment between Streptomyces griseus and S. tenjimariensis by the selection of clones with a unique antibiotic resistance. Nonantibiotic-producing mutants of streptomycin (SM)-producing S. griseus SS-1198 with resistance to SM and istamycin (IS)-producing S. tenjimariensis SS-939 with resistance to kanamycin (KM) were protoplasted, mixed with polyethyleneglycol and regenerated. Resistant clones to both SM and KM were found among spores of the regenerated culture at a frequency of 10^-6. Their growth appearance was identical with that of S. griseus. Antibiotic productivity was found only in clones resistant to both 20-50μg/ml of KM and 400μg/ml of SM. The antibiotic produced by a selected strain, SK2-52, proved to be different from SM and IS.

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A new antibiotic-producing Streptomyces strain SK2-52 obtained by a protoplast fusion treatment between Streptomyces griseus NP1-1 and S. tenjimariensis NM16 showed taxonomical features identical with those of S. griseus. The strain was resistant to wider range of aminoglycoside antibiotics than the parental strains. This multiple resistance corresponded to the activities of streptomycin kinase and acetyltransferase which were probably derived from S. griseus NP1-1. Clones with fast-growth and reduced antibiotic productivity frequently segregated from strain SK2-52, while their antibiotic resistance was stable. The results suggest that the fusion treatment caused a genetic change in S. griseus which enhanced the expression of genes for unique multiple resistance to aminoglycoside antibiotics and also induced new antibiotic production.

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The carbapenem antibiotics, which include the olivanic acids and thienamycin, possess potent broad spectrum antibacterial activity. They are however extensively metabolized by the renal dipeptidase enzyme, dehydropeptidase I. As a result of this degradation, only low urinary recoveries of antibiotic are obtained in vivo. The preparation of mutual pro-drugs of the olivanic acids and an inhibitor of the renal dipeptidase enzyme is described. MM 22382 and MM 13902 have been combined with Z-2-isovaleramidobut-2-enoic acid as double esters of formaldehyde hydrate. Administration of these linked esters to mice results in improved urinary recoveries of antibiotic.

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The synthesis of 6β-bromopenicillanic acid labeled with deuterium and tritium in the β-methyl group is described. The S-sulfoxide of benzyl- or p-methoxybenzyl 6α-bromopenicillanate is refluxed in benzene containing an excess of tert-BuOD, D₂O or HTO. After deoxygenation and deprotection of the ester, the labeled 6α-bromopenicillanic acid is epimerized (N, O-bis(trimethylsilyl)acetamide/1, 5-diazabicyclo[4.3.0]non-5-ene in CH₂Cl₂). The two epimerized are separated by column chromatography.

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On the assumption of the theory that the sulfone of a penam derivative should effectively act as a suicide substrate against β-lactamases to which the parent compound is a poor substrate, the action of cloxacillin sulfone on four different types of β-lactamases was studied. As we expected, cloxacillin sulfone showed strong mechanism-based irreversible inactivation against type Ib penicillinase and Proteus vulgaris cephalosporinase whereas it showed no progressive inactivation against cloxacillin-hydrolyzing type II penicillinase. However, an unexpected result was that cloxacillin sulfone could not inactivate Citrobacter freundii cephalosporinase which itself could hardly hydrolyze the parent cloxacillin. The number of hydrolytic events which occurred before inactivation of type Ib penicillinase, and P. vulgaris cephalosporinase, by the inactivator was 190 and 13, respectively. These values indicate that cloxacillin sulfone is far more effective as a suicide substrate against the two types of β-lactamases than penam sulfones so far reported. The inactivation proceeded via the formation of an irreversible enzyme-inhibitor complex which could be detected by isoelectric focusing.

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Pulmonary fibrosis in mice induced by peplomycin (PEP) was suppressed by administration of anti-inflammatory agents such as prednisolone and D-penicillamine during or after the administration of PEP. Pulmonary fibrosis was also suppressed by administration of cyclophosphamide, an immunosuppressive antitumor agent before, during or after the administration of PEP. The pulmonary fibrosis in athymic nude mice induced by PEP was less than that in normal mice. The low response in the nude mice was enhanced by transfer of thymocytes to the same level as that in the normal mice. This suggests that the immune system, especially thymus-dependent immunity, is involved in the pulmonary fibrosis induced by PEP.

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The bleomycins, phleomycins and tallysomycins are structurally similar glycopeptide antibiotics. Within each class, individual members differ only in the structure of a basic group. The antibiotic effect of phleomycin (Bristol batch A9331-648) against Escherichia coil is amplified substantially by a number of simple heterocyclic and aromatic compounds. In this paper a sample of 26 such compounds were tested for this property with 25 different phleomycins, bleomycins and tallysomycins. The nature of the variable basic group of the phleomycins, bleomycins and tallysomycins determined the response obtained with all amplifiers, although variation of response was much less marked with caffeine which potentiated the cytotoxic effects of all the phleomycins, bleomycins and tallysomycins tested. Phleomycins and bleomycins having two or three guanidino groups in the variable basic group, or phleomycins having a secondary amino group within a methylene chain and a terminal 2-phenylethyl substituent, were amplified by most compounds, whereas the cytotoxicity of others was enhanced little or not at all. Similar phleomycins, having a secondary amino and a terminal guanidino group and no 2-phenylethyl substituent showed little enhancement, and in these cases the inclusion of a 2-phenylethyl substituent had a major influence in determining amplifiability. Bleomycins and phleomycins having identical basic groups were amplified to similar extents by the sample of 26 amplifying agents used.

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