Sulfazecin, a new water-soluble acidic antibiotic, which is active against Gram-negative bacteria, was isolated as crystals from the culture broth of Pseudomonas acidophila G-6302 by use of anion exchange resin and activated charcoal. The molecular formula of sulfazecin was determined to be C₁₂H₂₀N₄O₉S from physicochemical data. The IR and NMR spectra suggested that this antibiotic has a β-lactam ring, methoxyl and sulfonate groups. On acidic hydrolysis it gave D-alanine and D-glutamic acid. These chemical and physicochemical data indicated that sulfazecin is a new β-lactam antibiotic.

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The epithienamycins are cell wall active antibiotics structurally related to N-acetylthienamycin. We have found forty-three isolates of Streptomyces flavogriseus which are capable of producing members of the epithienamycin family. Six major epithienamycin components, and xanthomycin, have been isolated from fermentation broth. Fermentation conditions can be varied to enrich for certain members of the epithienamycin family. All six components show activity in vitro versus a broad spectrum of bacterial species. The weight potencies vary 27 fold from the most active to least active.

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At least six distinct β-lactam antibiotics of the epithienamycin family are produced by a strain of Streptomyces flavogriseus MB 4638. Each of the six can be isolated in substantially pure form by column chromatography using Dowex 1, Amberlite XAD-2 and Biogel packings. The structures were established by comparison of the ultraviolet, proton magnetic resonance and mass spectral characteristics with those of thienamycin and its derivatives. All six compounds contain the carbapenem ring system which is also found in thienamycin. They differ from each other and from thienamycin by chemical modifications and/or stereoisomerism. Enzymatically deacetylated epithienamycin A has the properties of an isomer of thienamycin.

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A new antibiotic, reductiomycin was isolated from the culture broth of Streptomyces griseorubiginosus. The antibiotic has the molecular formula C₁₄H₁₅O₆N (M.W. 293). Reductiomycin is active against Gram-positive bacteria, fungi, and Newcastle disease virus.

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The structure of reductiomycin was elucidated as 2-hydroxy-5-oxo-1-cyclopentenyl (2E)-3-(5-acetoxy-2, 3-dehydropyrrolidin-3-yl) propenate by spectroscopic studies.

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A series of new biosynthetic derivatives of tallysomycins A and B were obtained by precursor amine-feeding fermentation. Certain diamines were incorporated into tallysomycins as the terminal amine moiety affording two classes of biosynthetic derivatives, with or without the β-lysine moiety in the subterminal position. Among 21 derivatives prepared, tallysomycin S_10b was selected for further studies in view of its favorable therapeutic indices.

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Tallysomycin S_10b is a biosynthetic derivative of tallysomycin B obtained by precursor amine-feeding fermentation. Tallysomycin S_10b contains 1, 4-diaminobutane as the terminal amine moiety in place of spermidine of tallysomycin B, and its assigned structure was verified by carbon-13 NMR spectrum. The antitumor activity of tallysomycin S_10b was comparable to that of tallysomycin A against Lewis lung carcinoma and B16 melanoma. Tallysomycin S_10b was more active than tallysomycin A against sarcoma 180 but less active than the latter against leukemia P388. Tallysomycin S_10b was less toxic than tallysomycin A in terms of acute and subacute LD₅₀ values. The nephrotoxic potential of tallysomycin S_10b in rats was less than that of tallysomycin A.

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The structure and stereochemistry of neplanocin A was determined on the basis of its spectral and chemical evidences as [1R-(1α, 2α, 3β)]-3-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)- 4-cyclopentene-1, 2-diol. For the final proof of the structure, X-ray crystallographic analysis of neplanocin A was carried out.

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Fortimicin analogs have been prepared via glycosylation of suitably protected derivatives of the aminocyclitol fortamine. The analogs contain changes in the sugar portion of the molecule and/or in the manner of its attachment to the cyclitol.

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The preparation of 4-de-N-methylfortimicin A analogs as well as the preparation of 4-de-N-methyl-4-N-(β-aminoethyl)-4-N-ethylfortimicin B is reported. It was shown that the 4-N-methyl group in fortimicin analogs is essential for antibacterial activity since neither the 4-de-N-methylfortimicin A nor the 4-de-N-methyl-4-N-(β-aminoethyl)-4-N-ethylfortimicin B exhibited useful biological activity.

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Gilvocarcin V, isolated from a Streptomyces culture showed activity against experimental tumors such as sarcoma 180, Ehrlich carcinoma, Meth 1 fibrosarcoma, MH134 hepatoma and lymphocytic leukemia P388. In particular, 40% of treated mice survived for 60 days, after intraperitoneal administration of gilvocarcin V to mice bearing Ehrlich ascites carcinoma.

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Cytotoxic effect of dactylarin on Ehrlich ascites carcinoma cells is caused by the inhibition of some SH-dependent glycolytic enzymes, especially of hexokinase (EC 2.7.1.1), glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) and 6-phosphofructokinase (EC 2.7.1.11). Dactylarin interacts with thiols, which explains its inhibitory effectiveness on the above glycolytic enzymes.

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A new derivative of rifamycin SV, R-75-1, inhibits RNA synthesis in Mycobacterium: smegmatis ATCC 607 (M607) at a concentration 10 times lower than rifampicin (RFP). However, both R-75-1 and RFP inhibit RNA polymerase reaction by 50% at the same concentration level (0.05-0.1 μg/ml). Both inhibit the initiation process of RNA synthesis. E. coli RNA polymerase of the RFP-resistant strain was resistant to R-75-1. RFP was not inactivated by M607 cell extracts. The inhibitory effect of R-75-1 is markedly diminished if mycobacteria are grown in the medium containing Tween 80. On the basis of these results. the greater activity of R-75-1 to mycobacteria is suggested to be due to the better permeability than RFP.

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In vitro activities of M-4365 G₂, a new basic 16-membered macrolide antibiotic, against a total 19 strains including human, bovine, porcine, rodent, avian and saprophytic mycoplasmas were compared with those of three other macrolide antibiotics, josamycin, erythromycin and tylosin. M-4365 G₂ exhibited stronger activities than the other macrolide antibiotics against 11 strains of mycoplasma tested. Especially, its higher activities against M. pneumoniae Mac and FH, U. urealyticum T-960, M. mycoides PG-1 and M. gallisepticum Kp-13, PG-31 and 9-49A were to be noticed (final minimum inhibitory concentrations: 0.0001-0.049μg/ml). Higher antimycoplasmal activity of M-4365 G₂ than that of tylosin was also proved in experimental treatment of chickens intranasally inoculated with M. gallisepticum Kp-13 by feeding a diet containing the drug. M. gallisepticum Kp-13 was not isolated from the infected chickens fed a diet containing 0.0063% or more of M-4365 G₂.

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The effect of cefsulodin in combination with mecillinam was examined against a wide range of bacterial species. The antibacterial spectrum was widened by the combination of cefsulodin and mecillinam in the ratio of 5: 1 and 10: 1. In overall observations, in the in vitro test, a synergistic effect against clinical isolates was found on Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Serratia marcesscens, Proteus mirabilis and Proteus vulgaris, and an additive effect was found on Staphylococcus aureus, Escherichia coli, Proteus morganii, Proteus rettgeri, Proteus inconstans and Pseudomonas aeruginosa. In in vivo tests, a synergistic effect was observed on S. marcescens TN 66 and K. pneumoniae DT infections and an additive effect was observed on S. aureus 308 A-1, E. coli O-111 and T-7, C. freundii TN 518, E. cloacae TN 603, P. vulgaris GN 4712, P. morganii TN 373 and P. aeruginosa U 31 infections.

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In vitro and in vivo synergistic effects of cephalexin and mecillinam against Escherichia coil, Klebsiella pneumoniae, Enterobacter sp., Serratia marcescens and Proteus sp. were demonstrated and their action mechanism were also discussed. The growth curve after the exposure of cephalexin and mecillinam at the concentrations at which these antibiotics had no effects when given alone showed a decrease of the turbidity and the presence of a bactericidal effect. In experimental infection in mice, the combination of both drugs showed a synergistic effect and excellent therapeutic effect. The blood concentration ratio of cephalexin to mecillinam was coincident with the concentration ratio of these antibiotics at which the synergistic effect was observed in vitro. Phase-contrast and scanning electron micrographs of bacterial cells exposed to the combination of cephalexin and mecillinam showed somewhat elongated bacteria and formation of spindle cells with swelling in the central part. A leakage of the cellular contents from part of the swelled cell wall was observed by transmission electron microscope. Cephalexin showed an affinity for penicillin binding proteins (PBPs)-1a and 3 in Escherichia coli and mecillinam showed an affinity for PBP-2. When these antibiotics were used concurrently, they exerted an additive effect to increase the affinity for PBPs. The lytic activity was increased much more after the combination of two antibiotics than after a single exposure.

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The drug-protein interactions between cefoperazone (CPZ) and apalcillin (APPC), and between cefazolin (CEZ) and APPC were investigated in in vitro and in vivo experiments. Though the binding rates of CPZ or CEZ to rabbit serum and human serum albumin subsided remarkably with increased drug concentrations, APPC was not greatly affected, even at high concentrations. It appeared that APPC had a higher binding capacity to protein than CPZ or CEZ. From the results of competitive study, it became clear that APPC partially shared the binding sites on protein with CPZ or CEZ. The CPZ or CEZ serum levels in rabbits administered together with APPC were not different from those for the single administration, but APPC levels for the simultaneous administration were slightly lower.

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The drug-protein interactions between cefoperazone (CPZ) and novobiocin (NB), and between cefazolin (CEZ) and NB were investigated. Though there was a remarkable reduction of CPZ or CEZ binding to rabbit serum and human serum albumin with increases in drug concentrations above 3.0×10-4 M (CPZ: 200 μg/ml, CEZ: 140 μg/ml), NB binding was not affected. In addition, when CPZ or CEZ was added to the NB solution, NB binding was not altered and remained above 90%. Therefore, it was evident that NB had a high capacity for binding to protein, compared with CPZ or CEZ. From the competitive study, the main binding site of NB to protein appeared to differ from that of CPZ or CEZ. The CPZ or CEZ serum levels in rabbits for the simultaneous administration of NB were significantly higher than those for the control experiments, however, the NB serum levels were not greatly affected by CPZ or CEZ. We have reported the drug-protein interactions in vitro and in vivo between antibiotics, i.e, between cefoperazone (CPZ) and cefazolin (CEZ)1), and between apalcillin (APPC) and CPZ or CEZ2). Our reports have shown that the binding behavior of CPZ to serum protein is similar to that of CEZ, however, APPC is somewhat different from CPZ or CEZ.

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The degrees of bindingo f [³H]dibekacin to LiCl-treated cores of E. coliribosomes were Reduced by increasing LiCl concentrations. The 1.15M LiCl core lost 70-80% of the original binding capacity. The antibiotic attachment to the 1.15 M LiCl core was restored by reconstitution with the split proteins (SP), which were obtained by the treatment of 70S ribosomes with LiCl at concentrations of 0.8-1.15 M. The basic proteins, split off during the transition from 0.4 M LiCl core to 0.8-1.15 M LiCl core, seemed to be involved in the drug binding. SP_0.4-1.15, which was obtained by the treatment of the 0.4 M LiCl core with 1.15M LiCl, was Fractionated by CM-Sephadex C-25 column chromatography, and each fraction was assayed for protein composition and the capability of restoring the ability of the 1.15M LiCl core to bind the drug. Of ribosomal proteins eliminated with 1.15 M LiCl, the addition of either S9 or L6 alone to the 1.15M LiCl core was observed to restore approximately 50% of the binding as compared to the 70S ribosome alone, and both proteins restored about 70% of the binding. The results suggested that ribosomal proteins S9 and L6 were involved in the attachment of [3^H]dibekacin to the ribosome. The antibiotic binding to the 70S ribosome and 1.15M L iCl core reconstituted with S9 or L6 was considerably inhibited by unlabelled dibekacin or kanamycin, and partially inhibited by gentamicin or neomycin, but was not significantly affected by streptomycin or viomycin.

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