A novel, chlorine containing sulfamoyl nucleoside antibiotics, AT-265, was found from Streptomyces rishiriensis subspecies and its structure and biological activities were determined, The antibiotic is active in vitro against some Enterobacteriaceae and some Gram-positive bacteria.

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Kirrothricin, a new narrow-spectrum antibiotic produced by Streptomyces cinnamomeus strain Tü 89, was isoiated in respect to Its activity against Clostridium pasterurianum The molecular formula is C₄₄H₆₄N₂O₁₀. Kirrothricin is related to kirromycin, aurodox and other members of this group by its chemical structure, biological activity and the mode of action.

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A new carbapenem antibiotic, C-19393 E₅, was isolated from the culture filtrate of Streptomyces griseus subsp. cryophilus C-19393 as a minor component. The chemical structure of the antibiotic was determined by comparing its spectral data with those of the known 5, 6-cis carbapenem antibiotics and confirmed by partial synthesis from epithienamycin B as shown in Fig. 1.The antibiotic has a broad antimicrobial spectrum and shows strong inhibitory activity againstβ-lactamases.

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Twelve 5, 6-cis-carbapenem antibiotics were examined for their β-lactamase inhibitory activities, their types of inhibitions, and their synergistic activities with other β-lactam antibiotics. All the carbapenems inhibited eight types of β-lactamases including cephalosporinases which were insensitive to clavulanic acid and sulbactam. The sulfonyloxy ethyl carbapenems were the most active inhibitors; they inhibited all β-lactamases in a progressive fashion, whereas some of the hydroxyl compounds exerted non-progressive inhibition against several β-lactamases such as those of Escherichia coli TN713 and Proteus vulgaris GN4413. Several carbapenems were inactivated by the β-lactamases of Citrobacter freundii GN1706, P. vulgarisGN4413, E. coli TN713, and Klebsiella pneumoniae TN1698. Most of the carbapenems potentiated the antibacterial activities of ampicillin and cefotiam against β-lactamase-producing bacteria.

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A novel antibiotic, prothracarcin was isolated from the culture broth of Streptomyces umbrosus subsp. raffinophilus DO-62. The antibiotic has the molecular formula of C₁₄H₁₄N₂O and belongs to the pyrrolo [1, 4]benzodiazepine antibiotics. Its structure has been elucidated by mass and NMR spectra. It is active against Gram-positive and Gram-negative bacteria and experimental murine tumor sarcoma 180 and leukemia P388.

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New components of tetrocarcins (E₁, E₂, F and F-1) were found in the culture broth of Micromonospora chalcea KY 11091 that was known to produce tetrocarcins A, B and C Tetrocarcin F-1 consisted of tetronolide and nitro sugar (tetronitrose). Tetrocarcins E₁ and E₂ consisted of F-1 and deoxy sugar (L-digitoxose). Tetrocarcin F consisted of F-1 and two deoxy sugars (their structures were not yet determined). They all showed antibacterial activities against Gram-positive bacteria and the specific activity decreased with decrease in the numbers of deoxy sugars attached to the aglycone.

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3-Mcthoxy-2, 5-toluquinolle (I), described in the literature as a synthetic intermediate, was isolated for the first time from a natural source namely the fermentation broth of an Aspergillus strain. The compound showed moderate activity against various Gram-positive and Gram-negative bacteria.

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The three polyene macrolide antibiotics fungichromin, lagosin, and cogomycin, previously described as having some stereochemical differences at one or more centers, are shown by countercurrent distribution, high-performance liquid chromatography, carbon-13 nuclear magnetic resonance spectroscopy, circular dichroism, and biological studies to be identical in all respects, including stereochemical aspects. The differences observed earlier in their properties have now been ascribed to varying amounts of impurities, which are separable by high-performance liquid chromatography. All three antibiotics contain one major and several minor components.

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Partricin, a heptaene macrolide antibiotic, has been separated into three polyene components, partricins A, B and C, and one non-polyene component by countercurrent distribution. Treatment of partricin with base gave p-(methylamino)acetophenone andp-aminoacetophenone from partricins A and B, respectively, identifying both as members of the aromatic subgroup of the heptaene antibiotics. Both partricins A and B yield mycosamine on mild acid hydrolysis. NMR and mass spectral studies on products of ozonolysis or hydrogenolysis of acetyl derivatives provided evidence for the partial structures 1-9.

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The morphological, cultural, physiological and biochemical characteristics of a new actinomycete strain producing a new antibiotic, setamycin are described. The strain forms aerial mycelia. There is no fragmentation of vegetative mycelia. Since the cell wall type is a new one containing both LL-and meso-2, 6-diaminopimelic acid, glycine and galactose, strain KM-6054 could not be classified in any previously named genera of the order, Actinomycetales. Thus, it is considered to be a member of a new genus, for which the name Kitasatosporia is proposed. The type species (monotype) of this genus is K.setalba. The type strain of K. setailsb as train KM-6054(ATCC 33774).

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Streptomyces tenebrarius ISP 5477, which produces nebramycins, was highly resistant to the following aminoglycoside antibiotics: neamine, ribostamycin, butirosin A, neomycin B, paromomycin, kanamycin A, dibekacin, gentamicin C complex, lividomycin A, istamycin B and streptomycin. Polyphenylalanine synthesis on the ribosomes of this strain was highly resistant to neamine, ribostamycin, butirosin A, kanamycins A, B and C, dibekacin, gentamicin C complex and istamycin B, moderately resistant to lividomycin A and streptomycin, but sensitive to neomycin B and paromomycin. Moreover, cell free extract of the strain contained phosphotransferase and N-acetyltransferase. The former enzyme was confirmed to be an aminoglycoside 6-phosphotranstrase which inactivated streptomycin; the latter inactivated kanamycins B and C, dibekacin, neamine, neomycin B, paromomycin, lividomycin A, butirosin A and ribostamycin, but did not inactivate kanamycin A, gentamicin C complex and sagamicin, suggesting an aminoglycoside 2'-acetyltransferase. These results indicated that the high resistance or S.tenebrarius ISP 5477 to a wide range of aminoglycoside antibiotics is due to ribosomal resistance and to the inactivating enzymes, aminoglycoside N-acetyltransferase(s) and aminoglycoside 6-phosphotmnsferase.

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A thirteen-fold excess of dithiothreitol maintainsδ(L-α-aminoadlpyl)-L-cysteinyl-D-valine (ACV) in its monomeric form under the conditions normally encountered in an ACV cyclization assay system, using Streptomyces clavuligerus. A reversed phase high performance liquid chromatographic(HPLC)system which separates ACV monomer from isopenicillin N, penicillin N and from other cyclization assay components has been developed as follows; mobile phase: 5% methanol-95% KH2PO4(0.05 M adjusted to pH 4.O with concentrated H3PO4; stationary phase:μBondapak-C18; flow rate: 2ml/minute for 51ninutes, 3ml/minute for the remainder; detection: 220 nm), Under these conditions, authentic samples of isopenicillin N and penicillin N elute with a retention time of 5.25 minutes, which coincides with a peak of newly-formed material observed in cyclization reaction mixtures. The combined concentration of isopenicillin N and penici11in N[(iso)penicillin N]in cyclization reaction mixtures corresponds closely to the concomitant decrease in the ACV monomer. Cyclization reaction mixtures, in which crude cell-free extract from S. clavuligerus NRRL 3585 is the enzyme source, contain(iso)penicillin N at a concentration of 43.31μg/ml after a 1-hour incubation period. Cyclization reaction mixtures, in which salt-precipitated cell-free extract from S. clavuligerus is the enzyme source, contain 39.0μg/ml(iso)penicillin N.

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Tetrocarcin A, isolated from a Micromonospora culture showed activity against experimental i.p. inoculated tumors such as Ehrlich carcinoma, MH134 hepatoma, B16 melanoma. But it was not active against solid tumors such as sarcoma 180 and Ehrlich carcinoma. It was marginally active against the growth of solid Lewis lung carcinoma without prolonging the life span of the tumor-bearing mice. It was active against P3881eukemia(i.v.-i.v. system). It did not show myelosuppression and nephrotoxicity in mice. DNA and protein synthesis of P388 cells in culture were more significantly suppressed than RNA synthesis by tetrocarcin A.

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The mode of action of gilvocarcins was studied. Gilvocarcins V, M and A possessed antibacterial activities decreasing in that order, Gilvocarcin V inhibited DNA synthesis in Bacillus subtilis through strong interaction with DNA and resulting cleavage. Gilvocarcin M showed interaction with DNA and a small change in DNA mobility upon electrophoresis in agarose gel. While gilvocarcin A showed no interaction with DNA, thus reflecting their relative biological activities.

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The oral administration of forphenicinol, S-2-(3-hydroxy-4-hydroxymethylphenyl)glycine which was synthesized during the study of derivatives and analogs of forphenicine, augmented delayed-type hypersensitivity to sheep red blood cells and oxazolone in mice. The treatment with forphenicinol restored DTH in mice immuno-suppressed by cyclophosphamide to normai response. Forphenicinol neitller augmented antibody-formation nor stimulated proliferation of lymphocytes in the presence or absence of lectins. Phagocytosis by peritoneal macrophages was enhanced by forphenicinol in vivo and in vitro. Forphenicinol was effective in increasing the production of CFU-C in the presence of colony stimulating factor and partially prevented the reduction of leucocyte counts caused by mitomycin C.

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The antitumor activities of forphenicinol against murine transplantable tumors were examined, Ehrlich carcinoma was suppressed by treatment with O.08-0.31 mg/kg/day of for-phenicinol given for 10 days starting 5 days after tumor inoculation. IMC carcinoma was also suppressed by treatment with O.5-5mg/kg/day given for 5 days starting 8 days after the inoculation. The antitumor activity was dependent on the number of tumor cells inoculated, schedule of administration and dose. However, even in case of fast growing tumors such as L1210 and inoculation with a large number of tumor cells, forphenicinol markedly enhanced the antitumor effect of 6-mercaptopurine, aclacinomycin and cyclophosphamide. Forphenlcinol showed a protective effect on Pseudomonas infection in mice.

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The immuno-suppressive activities of 7-N-(p-hydroxyphenyl)mitomycin C[M-83], a derivative of mitomycin C(MMC), which has better antitumor activity against murine tumors, was investigated in mice. A single injection of M-83 induced an apparent but relatively transient reduction in both plaque-fbrming cell production and delayed type hypersensitivity reaction to sheep red blood cells. The suppressive effect of M-83 was significantly milder than that of MMC at the same effective and molar equivalent doses. Moreover, the recovery from immunosuppression induced by M-83 was also relatively rapid as compared with MMC. The inhibiting activity of M-83 against the blastogenic response of spleen cells was milder in vitro, but was more significantly cytotoxic in vitro than that of MMC.

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Alanine peptides were attached to the desosamine hydroxyl group of erythromycin A and to the 9-amino group of 9-(S)-erythromycylamine in an attempt to facilitate transport of the antibiotic into Gram-negative bacterial cells. Antibacterial activity and ribosome binding data are reported for these compounds.

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The efficiency in inducing cation permeability of vacidin A, candicidin D and amphotericin B has been compared on small and large lipidic vesicles. Amphotericin B is two times less effective on large than on small vesicles, On the contrary, vacidin A and candicidin D are about ten times more effective on large than on small vesicles. These data are consonant with what js observed on living cells.

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The synergistic effect of a β-lactam antibiotic in combination with a β-lactamase inhibitor (cloxacillin) on Gram-negative bacteria producing various types of β-lactamases was studied with respect to the properties of the enzymes by usinga set of bacterial strains we had developed previously for evaluation of β-lactamase stability ofβ-lactam antibiotics1). Cloxacillin showed strong synergy in combination with ampicillin or cephalosporins against typical cephalosporinase-producing bacteria, but not against penicillinase-producing bacteria. Analysis of the results indicated that the efficacy of a competitive inhibitor such as cloxacillin is greatly influenced by the following factors: the affinity or the inhibitor for the enzyme, the difference between the affinity or the inhibitor for the enzyme and that of the combined antibiotic for the enzyme, and the ability of the inhibitor to penetrate the bacterial outer membrane. It was also demonstrated that this information concerning the efficacy of an inhibitor could easily be obtained by using the set of bacterial stra1ns and the methods described.

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Nanaomycin (NNM) D had a higher growth inhibitory activity than NNM-A against a Gram-negative marine bacterium, Vibrio alginolyticus. These quinone antibiotics were reduced by the respiratory chain-linked flavin dehydrogenase of the organism and the reduced forms of NNMs were quickly autoxidized by molecular oxygen to produce superoxide radicals(O₂-). NNM-D was more effective than NNM-A both ill the induction of KCN-insensitive oxygen consumption with the intact cells and in the production of O₂- by the redox cycling. The growth inhibitory activities of NNM-D and A were partly reduced by raising the superoxide dismutase level of the cells. Thus, the ability to produce O₂- at the ce11 membrane was correlated to the antibacterial activities of NNM-D and A.

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The occurrence in β-lactam treated patients of unstable L-forms of Pseudomonas aeruginosa insensitive to various antibiotics and synergistic effect of combined action of cell wa11-affecting antibiotics and macrolide on Pseudomonas infection led us to examine the effects of macrolide on P. aeruginosa pretreated with cell wall-affecting antibiotics. The effects of macrolide antibiotics such as midecamycin acetate (MOM) on P. aeruginosa was investigated, a rapid killing effect by MOM was noted after treatment with suboptimal doses of cell wall-affecting antibiotics such as polymyxin B, carbenicillin, dibekacin or fosfomycin. Incorporation of [¹⁴C]MOM into intact P. aeruginosa cells was not significant, but was apparent into L-form cells or cells pretreated with cell wall-affecting antibiotics, The incorporated radioactlvity was found in the 70 S ribosome fraction, binding with the 50 S subunits of ribosome in both cases. These results indicate that under certain conditions a macrolide antibiotic can enter the P. aeruginosa cell.

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The pharmacokinetics of neothramycin (NTM) was performed in mice, rabbits and man. Biological half-life of NTM in man after a 20 mg bolus injection produced an α phase half-life of 3.63 minutes, aβ phase half-life of 84.5 minutes and a volume of distribution at a steady state of 50.3 liters/body. Its human half-life was longer than those of adriamycin, mitomycin C and neocarzinostatin, and a little shorter than that of bleomycin. In mice and rabbits, NTM was well distributed in the kidney, urinary bladder, squamous tissues, lung, spleen and gastrointestinal tract and it was rapidly excreted in urine and bile. It was partially absorbed from the gastrointestinal tract. Concentrations of NTM in ascites and pleural fluids in man were also reported.

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