Spenolimycin, a new spectinomycin-type antibiotic, was discovered in the fermentation broth of a new actinomycete named Streptomyces gilvospiralis sp. nov. strain AB634D-177. Although a small amount of spectinomycin is coproduced by strain AB634D-177, the culture is different from other known spectinomycin-producing actinomycetes. Spenolimycin was obtained by conventional submerged culture in 14-liter fermentors with a peak antibiotic titer of 140 μg/ml.

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A new water-soluble, basic antibiotic has been isolated from the fermentation beers of Streptomyces gilvospiralis sp. nov. The structure of the antibiotic has been deduced from spectral studies and confirmed by chemical degradation to spectinomycin. This structure, 3'-O -methylspectinomycin-3', 4'-enol ether has led to the name spenolimycin.

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Spenolimycin is a new spectinomycin-type antibiotic isolated from Streptomyces gilvospiralis sp. nov. In vitro, it was active against a wide variety of aerobic Gram-positive and Gramnegative bacteria and Neisseria gonorrhoeae. It was two to four-fold more active against N. gonorrhoeae than spectinomycin. Spenolimycin was effective in the standard mouse protection test against Escherichia coli, Klebsiella pneumoniae and Streptococcus pneumoniae.

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Three Gram-negative bacteria produce new cephem antibiotics, named cephabacins, with unique 3-side chains. Cephabacins include F group antibiotics with a 7-formylamino substituent and H group antibiotics without the substituent. The producing bacteria were taxonomically characterized and designated as Lysobacter lactamgenus sp. nov. YK-90 and Xanthomonas lactamgena sp. nov. YK-278 and YK-280.

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Fifteen components of new antibiotics, cephabacins, were isolated from the culture filtrates of Lysobacter lactamgenus YK-90, Xanthomonas lactanigenaYK-280 and X. lactaingena YK-278. They were purified by column chromatography using cation-exchange resins, activated carbon, high porous resins and cation-exchange Sephadex and by preparative reverse-phase HPLC. The basic, water-soluble antibiotics were characterized as having a cephem skeleton and oligopeptide(s) as a side chain constituent from their spectroscopic analyses and amino acid analyses.

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The structures of 15 new cephem antibiotics, cephabacin F_1-9 and H_1-6, were determined by their spectroscopic analyses and decomposition studies. They are consisted of a cephalosporin nucleus and a di, tri or tetrapeptide including a new amino acid which is bound at the position 3 with an ester bond. The components, F_1-9, showed unique biological activities by the presence of a formylamino group at the position 7.

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Cephabacin F group antibiotics with a 7-formylamino substituent showed antibacterial activity against a wide variety of bacteria including β-lactamase-producing clinical isolates and anaerobic bacteria. Cephabacin H group antibiotics without the substituent showed more potent activity against Gram-positive bacteria than cephabacin F group antibiotics, but were not active against Gram-negative bacteria producing β-lactamases. Cephabacin F group antibiotics were highly resistant to hydrolysis by various types of β-lactamases and showed strong inhibitory activity against a cephalosporinase of Proteus vulgalis GN 4413 due to the 7-formylamino substituent. Mode of action of cephabacin F₁ and H₁ was examined using Escherichia coli and Bacillus subtilis as the test organisms. They showed strong lytic activity against these organisms and inhibited their peptidoglycan synthesis. Cephabacin F₁ had the highest affinity for penicillin-binding protein (PBP) 1 in E. coli and PBP 4 in B. subtilis. Cephabacins showed a protective effect in experimentally infected mice.

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The isolation of two new antibiotics, PD 114, 759 and PD 115, 028, exhibiting in vivo antitumor activity at extremely low doses is described. The physico-chemical properties of these sulfur-containing compounds show that they represent a novel class of antitumor agents.

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Irumamycin is a new 20-membered macrolide antibiotic isolated from a culture broth of a soil isolate which was named Streptomyces subflavus subsp. irumaensis AM-3603. It is active in vitro against some phytopathogenic fungi, but inactive against most aerobic and anaerobic bacteria and mycoplasmas. The potent in vitro activity and the results of preliminary pot tests indicated that the antibiotic is practicable as an agricultural antifungal agent.

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A new aminosugar named nojirimycin B (1) has been isolated as its bisulfite adduct from the culture broth of Streptomyces lavendulae SF-425, together with nojirimycin. Microbiological oxidation of 1 with Gluconobacter suboxydans IAM 1829 gave a δ-lactam (2). The structures of 1and 2 were determined to be 5-amino-5-deoxy-D-mannopyranose and D-mannonic-δ-lactam, respectively, on the basis of ¹H NMR spectroscopy and X-ray structural analysis. Both 1 and2 exhibited powerful inhibitory activity against rat epididymal α-mannosidase and apricot β-glucosidase.

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"Curing" treatment of a rifamycin -producing Nocardia sp. resulted in a mutant deficient in the synthesis of antibiotics. This deficiency was reversed in a medium containing yeast extract. The active substance, named B-factor, which induced rifamycin production in the mutant was purified from yeast extract, and its structure, 3'-(1-butylphosphoryl) adenosine, was determined by structural analysis and chemical synthesis. An extremely low concentration of B-factor (10 ng/ml) caused recovery of rifamycin B synthesis in the mutant and stimulated synthesis of the antibiotic in the parental strain.

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The absolute configuration of the ring system of the antibiotic G7063-2 has been established as being the same as that reported for terreic acid, based on circular dichroism data. During structure elucidation experiments, reaction with ethereal diazomethane gave an adduct whose structure is proposed.

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The complete structures of bacillomycin D and bacillomycin L were revised by FAB mass spectrometry and by Edman degradation of the derivatives resulting from the N-bromosuccinimide reaction. The homologous components of both series of antibiotics were separated by HPLC and the β-amino acids were identified by capillary gas chromatography.

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Commercial colistin (polymyxin E)-complex was separated into two major components (colistins A and B) on a preparative scale by HPLC (alkyl bonded silica and aqueous-organic mobile phase containing 0.2 M NaCl-HCl buffer (pH 2.0)). Desalting of the colistins A and B fractions was completed by reversed-phase adsorption and elution using methyl alcohol. In these experiments, it was inadvertently found that prolonged elution with water gave two hydrophilic peptides, which were tentatively named colistins A_H and B_H, respectively. Further elution with methyl alcohol produced two lipophilic peptides which were named colistins A_L and B_L. Colistin BH showed higher potency than colistin A_H, A_L or B_L, and it was also effective in vivo. The fatty acid and amino acid composition of colistin B_H was identical with that of colistin B_L, but colistin B_A contained a relatively large amount of nonionic sodium which scarcely responded to the sodium ion-selective electrode of an ion meter; colistin B_H had a slightly lower molar extinction coefficient than the colistin B_L which contained negligible amount of nonionic sodium. Colistin A_H also contained nonionic sodium. Potassium containing colistins could also be derived from colistin-complex. These compounds could not be formed merely by adding sodium chloride or potassium chloride to colistin-complex solution. To obtain the sodium-containing compounds, contact with some hydrophobic stationary phase, such as alkyl-bonded silica or styrene-divinylbenzene copolymer, was necessary. It is postulated that one of the antibacterial mechanisms of polymyxin is associated with its complex-forming action on monovalent cations after contact with the lipid layer of the bacterial outer membrane.

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Two series of new semisynthetic rifamycin SV derivatives have been prepared. One of them bears a quaternary ammonium salt at C₃ (1-5). and the other a pyridoimidazo system condensed at C₃ and C₄ (6-11). While compounds 1-5 had poor antibacterial activity in vitro, compounds 6-11 were found to be highly active in vitro but poorly absorbed in vivo. They could thus have potential as agents in the therapy of intestinal infections. The synthesis and the ¹H NMR structure determination of these new compounds are reported.

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This paper reports the determination of the X-ray molecular structure of 4-deoxy-3'-bromopyrido[1', 2'-1, 2]imidazo[5, 4-c]rifamycin S, carried out in order to unequivocally define the general structure of a new series of rifamycin SV derivatives, which are potent antibacterial agents, and are not absorbed at the gastroenteric level. They have been prepared by Alfa Farmaceutici, Bologna, by condensing 2-aminopyridine derivatives to 3-bromorifamycin S. The solid state X-ray study has confirmed the structure proposed on the basis of ¹H NMR studies in solution. It has also shown that the newly formed pyridoimidazo system is in a mesomeric betaine form, the pyrido nitrogen being positively charged and the imidazo nitrogen being negatively charged.This feature is believed responsible for the pharmacokinetic behavior of these new drugs, one of which, denoted either as rifamycin L 105 or rifaximin, is actually under clinical trial as a topical intestinal disinfectant.

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Derivatives of mycaminosyl tylonolide (1) and 4'-deoxymycaminosyl tylonolide (2) containing N-ethyl-2-fluoro-, 2, 2-difluoro- and 2, 2, 2-trifluoroethylamino groups at their C-23 have been prepared by treating 23-deoxy-23-ethylaminomycaminosyl tylonolide diethyl acetal (14) and its 4'-deoxy analog 15 with 2-fluoro-, 2, 2-difluoro- and 2, 2, 2-trifluoroethyl trifluoromethanesulfonates. The relationship between the antibacterial activity and the numbers of the fluorine atoms introduced in the final products is discussed.

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3'-Deamino-4'-epi-3'-hydroxy-daunorubicin (11) and -doxorubicin (14) have been synthesized.In the in vivo murine P-388 lymphocytic leukemia assay, these two compounds were more active than daunorubicin (1) and doxorubicin (2), respectively. Comparative studies in the P-388 assay indicated 3'-deamino-3'-hydroxydoxorubicin (3) to be more active than its 4'-epimer 14.

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Molecular orbital calculations by the CNDO/2D method yield charge distributions which correlate well with the observed ¹³C NMR chemical shift for the amide carbon of acylamino side chains of cephalosporins. Acyl groups that withdraw electrons from the amide C-N bond and concomitantly make the amide nitrogen more negatively charged increase the chemical shift. The trends are related to the degree of amide resonance. No direct correlation was found between the chemical shift of the amide carbon and the antibacterial activity of the cephalosporins.

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The biosynthesis of maduramicin α and β in a culture of Actinomadura yumaensis has been studied using ¹³C, ¹⁴C and ¹⁸O labeled precursors. The α component of this recently discovered polyether antibiotic, containing forty-seven carbon atoms in a seven-ring system, is derived from eight acetate, seven propionate and four methionine molecules. The β component which is missing one methoxy group incorporates three methionine methyl groups. The carbohydrate moiety was enriched by methionine, but not significantly by acetate or propionate. Studies of the incorporation of ¹³C labeled precursors permit the ¹³C NMR assignment of maduramicin. The origin of oxygen atoms of maduramicin has been examined by feeding [1-¹³C, ¹⁸O₂]acetate and [1-¹³C, ¹⁸O₂]propionate separately in the fermentation culture and the resulting doubly labeled maduramicin samples were analyzed by the isotopic shifts in the ¹³C NMR spectra. These results are consistent with the initial formation of a triene, which is converted to maduramicin by cyclization of the triepoxide.

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Biosynthesis of astromicin, a unique pseudodisaccharide aminoglycoside antibiotic containing 1, 4-diaminocyclitol component, was investigated by isolating a variety of possible precursor compounds from mutants of Micromonospora olivasterospora in which biosynthetic pathways for astromicin were blocked. Washed mycelia of M. olivasterospora mutants converted these compounds to astromicin, which was detected by thin-layer chromatography. Since astromicin possesses one glycyl and three methyl groups, [¹⁴C]glycine and [¹⁴C]methionine should be incorporated into precursors to form astromicin. To confirm the biosynthetic pathway, formation of labeled astromicin from the precursors was examined using [1-¹⁴C]-glycine or [methyl- ¹⁴C ]methionine. From above results, we propose the biosynthetic pathway for astromicin as shown in Fig. 2.

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An inosamine-idiotrophic mutant, KY11559, which produced no astromicin unless scyllo-inosamine was added to the fermentation medium, was isolated from Micromonospora olivasterospora. Biotransformation studies were performed with resting cells of this mutant and compounds assumed to be precursors of 1, 4-diaminocyclitol (fortamine). Scyllo-inosose, scyllo-inosamine and FU-10 were converted to astromicin. A number of mutants blocked in the biosynthesis of astromicin were developed from M. olivasterospora, and the intermediates accumulated by these mutants were isolated and identified. Twenty-five blocked mutants were classified into 10 groups, based on their complementation patterns by cosynthesis experiments. Further, utilizing these blocked mutants and the isolated compounds, biotransformation analyses were performed. The results showed that the amination at position 4 in fortamine occurred after formation of the pseudodisaccharide. Subsequently, the aminosugar and aminocyclitol moieties were aminated, methylated, dehydroxylated, epimerized and acylated to produce astromicin. Thus it was demonstrated that the astromicin biosynthetic pathway has a unique feature which is not found in the biosynthesis of other aminoglycoside antibiotics.

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Synergistic activity of astromicin and an antipseudomonal β-lactam antibiotic such as piperacillin, cefsulodin or carbenicillin againstPseudomonas aeruginosawas demonstratedin vitroandin vivo. Synergyin vitrowas observed more often when astromicin was combined with piperacillin or cefsulodin than when it was combined with carbenicillin. The combination of astromicin with piperacillin showed a bactericidal activity againstPseudomonas aeruginosaat a bacteriostatic concentration of each antibiotic alone. The synergy observedin vitrowas reproduced against experimental mouse infections, and the astromicin-piperacillin or cefsulodin combination produced significantly greater protective effects than the single use of individual antibiotics.

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It was found that Serratia marcescens 43, Serratia proteamaculans 48 and Serratia sp. 45, all of which were clinically isolated, produced a new type of aminoglycoside acetyltransferase which acetylated amikacin at the 6'-amino group. 1-N-[(S)-3-Amino-2-hydroxypropionyl]-gentamicin B (HAPA-B, SCH 21420) and gentamicin C₂ were hardly inactivated by the enzymes and had effective antimicrobial activities against these strains both in vitro and in vivo. This kind of aminoglycoside acetyltransferase should be classified into a new group other than previously reported AAC(6') enzymes.

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Escherichia coli BM2195 is highly resistant to erythromycin by inactivation of the antibiotic. We have determined the structure of the modified antibiotic by physico-chemical techniques including mass spectrometry, infrared spectrophotometry, ¹³C nuclear magnetic resonance, and circular dichroism. The results obtained indicate that E. coli BM2195 resists erythromycin by the production of an erythromycin esterase which hydrolyzes the lactone ring of the antibiotic.

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Cellular uptake and cytostatic activity of 4'-O-tetrahydropyranyladriamycin (THP) in various sublines resistant to anthracycline antibiotics of mouse lymphoblastoma L5178Y, Chinese hamster ovary (CHO) and mouse leukemia P388 cells were studied. All the sublines resistant to adriamycin (ADR) showed slightly decreased uptake of THP as compared with each sensitive lines, but THP was still taken up much more quickly than ADR by each of the ADR-resistant cell lines. Efflux of both anthracycline glycosides from the ADR-resistant P388 cells was faster than that from the ADR-sensitive P388 cells. The percentage of THP retained at equilibrium was higher than that of ADR in both ADR-resistant and -sensitive P388 cells. Cytotoxicity of THP to ADR-resistant cell lines was considerably lower compared with that for each of the sensitive lines but THP inhibited growth of ADR-resistant tumor cells at a concentration about 10 times lower than that for ADR. Thus THP was taken up more quickly, effluxed more slowly than ADR from the ADR-resistant cells, and showed stronger cytostatic activity than ADR on the cells.

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The antibacterial activity of MT-141 against Escherichia coli and Proteus morganii in compromised mice was investigated and compared with that of latamoxef, cefmetazole and cefoxitin. The bactericidal activity of MT-141 in short-term contact with E. coli and P. morganii was markedly enhanced when combined with mouse serum, and the activity of MT-141 was greater than the activities of the three reference drugs. The antibacterial activities of MT-141 in the liver, spleen and kidney of neutropenic and Sarcoma 180 tumor-bearing mice infected with E. coli and P. morganii were superior to the activities of the reference drugs. MT-141 was more potent than cefmetazole and cefoxitin, and similar to latamoxef in potency against systemic P. morganii infection in Sarcoma 180 tumor-bearing mice.

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The activity of the aminothiazolyliminomethoxy cephalosporin cefodizime (HR 221) was compared to that of cefotaxime, cefuroxime and cefazolin in experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. Cefodizime exhibited high and long-acting levels in the blood and lung homogenates of infected mice; the blood and tissue concentrations obtained with the other cephalosporins tested were low by comparison. In the treatment of experimental Klebsiella pneumonia, cefodizime was superior to cefotaxime and cefuroxime. Counts of the number of viable bacteria present in the infected tissue showed that cefodizime exerted a more marked bactericidal effect than cefotaxime or cefuroxime. Hardly any therapeutic activity was seen with cefazolin.

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Studies concerning the activity of cefodizime (HR 221), on certain aspects of the immune response, were conducted. It was found that lymphocytes from Balb/c mice treated with 3 and 30 mg/kg/day of cefodizime display increased responsiveness to B-cell mitogens and specific antigens. Also, the amount of antigen specific antibody producing plaque forming cells was increased in these mice and was accompanied by a rise in the specific IgG haemagglutinin titer. These effects were not observed in lymphocytes obtained from NMRI mice that had been treated with cefodizime. Peritoneal macrophages from NMRI mice, treated with cefodizime prior to harvesting of the cells, contained increased levels of lysosomal enzymes, developed enhanced chemiluminescent reaction to stimuli and showed elevated pinocytosis rates. Furthermore, NMRI mice treated with cefodizime during the immunization, developed enhanced DTH-reaction, when challenged with the antigen (SRBC). The prophylactic treatment of Balb/c mice with cefodizime (2×30 mg/kg/day ip for 4 days) significantly prolonged the mean survival time of the animals after intravenous infection with Candida albicans 200/175 (16.7 days as against 3.5 days in the case of the controls). This stimulatory effect of cefodizime on the host defence system was not observed for NMRI mice. Treatment with latamoxef or cefoperazone under the same experimental conditions did not reduce the susceptibility of mice to C. albicans. The protective activity of cefodizime against C. albicans in Balb/c mice, may be due to the immuno-stimulatory activity of this agent.

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