New antibiotics, plusbacins A₁-A₄ and B₁-B₄, were isolated from the culture broth of a strain of Pseudomonas sp. These antibiotics were isolated as a complex by column chromatographies on Diaion HP-20 and silica gel, and then separated by HPLC. They are amphoteric in nature. The hydrochlorides are obtained as colorless powders, soluble in methanol and alkaline water. From their physico-chemical properties, these antibiotics are presumed to be acyloctapeptides containing a lactone linkage, and their differences occur in amino acid and fatty acid residues. The antibiotics are active against Gram-positive bacteria in vitro and in vivo.

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The constituent amino acids of plusbacins A₁-A₄ were determined to be two moles of L-trans-3-hydroxyproline and one mole each of D-threo-β-hydroxyaspartic acid, L-threo-β-phydroxyaspartic acid, D-allo-threonine, D-serine, D-alanine and L-arginine. In plusbacins B₁-B₄, one mole of L-trans-3-hydroxyproline is replaced by L-proline. The fatty acid residue of A₁ and B₁ was determined to be 3-hydroxy-tetradecanoic acid, for A₂ and B₂ to be 3-hydroxy-isopentadecanoic acid, for A₃ and B₃ to be 3-hydroxy-isohexadecanoic acid, and for A₄ and B₄ to be 3-hydroxyhexadecanoic acid. A lactone linkage was suggested to reside between L-threo-β-hydroxyaspartic acid and 3-hydroxy-fatty acid residues by degradation experiments. The amino acid sequences of plusbacins A₂ and B₂ were confirmed by Edman degradation of their deacylated products, and supported by mass spectrometric studies. From the above, structures of all components of plusbacins were concluded.

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Mersacidin (1) is a new peptide antibiotic containing β-methyllanthionine. It is classified as a member of the proposed lantibiotic group of antibiotics, and is produced by a species of Bacillus. Mersacidin has a molecular weight of 1, 824 (C₈₀H_12ON₂₀O₂₁S₄). The antibiotic is active against Gram-positive organisms including methicillin-resistant Staphylococcus aureus, but has no activity against Gram-negative bacteria or fungi.

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Mersacidin is a new peptide antibiotic of the proposed lantibiotic family. It is active in vitro and in vivo against Gram-positive bacteria including the methicillin-resistant Staphylococci. Its in vitro activity is less than those of vancomycin and erythromycin but it shows much higher activity in the in vivo system than can be expected from the in vitro testing results. A water soluble potassium salt has been prepared which has an activity profile similar to that of mersacidin, but has better in vivo activity against Streptococcus pyogenes than the parent compound.

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A novel nucleoside antibiotic, SF2457, was isolated from the fermentation broth of Nocardia brasiliensis SF2457. The structure of SF2457 was determined by degradation studies using alkaline hydrolysis and methanolysis. SF2457 is closely related to the amicetin group antibiotics. The antibiotic exhibited inhibitory activity against Gram-positive and Gram-negative bacteria.

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A novel antifungal antibiotic, TAN-950 complex, was isolated from the culture filtrate of Streptomyces platensis A-136 (IFO 14603, PERM BP-1786). The water-soluble amphoteric substances in this complex were purified by chromatography using ion-exchange resins, QAE-Sephadex and adsorptive resins and were designated TAN-950 A and TAN-950 A-E mixture. The molecular formula of TAN-950 A was determined to be C₆H₇N₂O₄Na for the sodium salt. This new amino acid antibiotic showed antifungal activity against Candida albicans in vitro and in vivo, and had low toxicity in mice.

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In screening for antifimgal inhibitors from fungi, four related antifungal agents have been isolated from the cultivation of Aspergillus fumigatus ATCC 20857. These agents were initially produced by the microorganism growing on a solid millet-based medium. A liquid medium containing both glucose and glycerol has also been developed in which these antibiotics are produced in two phases. These novel compounds, sphingofungins A, B, C, and D, show a limited spectrum of antifungal activity but were especially effective against Cryptococcus species.

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A Streptomyces strain labeled A14106 was isolated and found to produce a novel 20-membered macrocyclic lactam derivative, BE-14106, which exhibited both cytotoxic activity against murine tumor cell lines and antimicrobial activity.

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A new antitumor antibiotic, 3''-demethylchartreusin was isolated from the culture broth of Streptomyces chartreusis, as a minor component of crude chartreusin. It is structurally related to chartreusin, containing same aglycone of chartreusin, but different sugar moieties. 3''-Demethylchartreusin exhibits some potent inhibitory activities against murine tumors.

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A novel compound depudecin inducing the flat phenotype of ras- and src- transformed NIH3T3 cells at a concentration of 1 μg/ml was isolated from the culture broth of Alternaria brassicicola. Based on its spectroscopic characteristics and X-ray crystallographic analysis of its bis-(1S)-(-)-camphanate, the structure of depudecin was determined'to be (2R, 3S, 4S, 5E, lS, 8S, 9R)-2, 9-dihydroxy3, 4;7, 8-diepoxy-undeca-5, 10-diene.

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As a result of screening for inhibitors of glycerol-3-phosphate dehydrogenase, which may be effective to prevent corpulence, we isolated two inhibitors named adipostatin A and adipostatin B from the culture broth of Streptomyces cyaneus 2299-SV1. Their structures have been established to be 5-n-pentadecylresorcinol and 5-isopentadecylresorcinol, respectively. Adipostatin A and adipostatin B inhibited glycerol-3-phosphate dehydrogenase at the IC₅₀ values of 4.1 μM and 4.5μM, respectively. These compounds prevented triglyceride accumulation in 3T3-L1 cells at a concentration of the μM level.

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Two new platelet aggregation inhibitors, PI-200 and PI-201 were isolated from the fermentation broth of Streptomyces sp. A7498. PI-200 and PI-201 inhibited ADP-induced aggregation of rabbit platelets with an IC₅₀ of 3.8 × 10^-4M and 7.1 × 10^-4M, respectively.

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A new calcium blocker, designated leualacin, has been isolated from Hapsidospora irregularis. The compound inhibits the binding of ³H-nitrendipine, a well known synthetic calcium blocker, to cardiac Ca channel in a competitive manner, although its structure is completely different from dihydropyridines.

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The structure of leualacin was determined by MS and NMR analysis to be a cyclic depsipeptide consisting of L-leucine, L-N-methylphenylalanine, β-alanine, and R- and S-leucic acids.

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Screening of microbial fermentation broths for herbicidal activity led to the discovery of a novel polyketide, herboxidiene, from an actinomycete identified as a member of the Streptomyces chromofuscus cluster. A 14- to 20-fold increase in fermentation production of herboxidiene was achieved as a result of media optimization. Herboxidiene was purified using successive reverse phase C18 steps and Sephadex LH-20 chromatography. Its molecular formula, C₂₅H₄₂O₆, was determined by HRFAB-MS. Herboxidiene demonstrated exceptionally potent, selective, herbicidal activity against a variety of weed species and was inactive against wheat, even at rates as high as 5.6 kg/hectare.

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The pharmacokinetics of the broad spectrum cephem RU 29 246 and its prodrug-ester HR 916 B were investigated in mice, rats and dogs and compared to those of cefpodoxime proxetil, cefuroxime axetil and cefixime. HR 916 B is well absorbed following oral administration and efficiently converted to the antibacterially active form. In mice, mean peak blood levels of 31.1 μg/ml of the parent compound were recorded within 20 minutes after oral administration of a single dose equivalent to 40 mg/kg RU 29 246. The bioavailability calculated on the basis of the areas under the concentration-time curves (AUC) and the urinary recoveries was about 90%. In rats, peak blood levels of 14.5μg/ml were obtained 1 hour after an oral 20 mg/kg dose. The bioavailability was calculated as 70%. In dogs, 40% of an oral 10 mg/kg dose was recovered in the urine within 24 hours. C_max was 15.9μg/ml at 4.6 hours. Mean elimination half-lives of RU 29 246 were 0.35, 0.5 and 2.1 hours in mice, rats and dogs, respectively. After an oral HR 916 B dose equivalent to 50mg/kg of RU 29 246, tissue concentrations at 0.5 hour ranged between 0.8μg/g in brain and 95.7 μg/g in murine kidneys. These values of HR 916 B are similar to, or distinctly higher than, those of the reference compounds. Of the oral cephalosporins tested, HR 916 B had the most balanced antibacterial spectrum. With ED₅₀s of between 0.9 and 11.5 mg/kg against staphylococci, its activity was similar to that of the additional reference compound cefaclor and higher than that of cefuroxime. Cefixime and cefpodoxime proxetil displayed low antistaphylococcal activity or were inactive.
In septicemias with Enterobacteriaceae, cefixime and cefpodoxime proxetil were more potent than HR 916 B and cefaclor. Cefuroxime axetil was inactive against most of these infections. HR 916 B was also highly effective against murine lung infections caused by Klebsiella pneumoniae DT-S or Streptococcus pneumoniae 1147.

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A series of new 3-[(Z)-2-methoxycarbonylvinylthio]-7β-[(2-aminothiazol-4-yl)acetamido]cephalosporins (1) having various oxyimino groups (Z-form) at the α position of the C-7 side chain was synthesized and evaluated for antibacterial activity and oral absorption in rats. Of these, the cephalosporin (1a) with a hydroxyimino group in the C-7 side chain showed a potent antibacterial activity against Gram-negative bacteria and Gram-positive Staphylococcus aureus as well as good oral absorption in rats. The structure-activity relationships of 1 are also presented.

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The synthesis of new carbapenems having either a pyridiniopropyl group at the 2-position or a pyridinioethyl group at the 1-position is described, along with the preparation of their corresponding hydroxy and acetoxy analogs. The antibacterial activity, susceptibility to dehydropeptidase-I (DHP-I) enzyme and chemical stability of these new carbapenems are also reported. 2-Pyridiniopropylcarbapenem 4 was found to possess excellent antibacterial activity. It was more stable chemically and less susceptible to the DHP-I enzyme than the thio analog 3. 1-Pyridinioethylcarbapenem 5 showed significantly reduced antibacterial activity as compared to 2-pyridiniopropylcarbapenem 4.

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Totally synthetic analogues of siastatin B, optically active 2-acetamido-3, 4, 5-trihydroxypiperidines having the nitromethyl, aminomethyl and carboxyl branched groups at C-5 have been obtained from D-ribono-1, 4-lactone by a stereospecific convergent method. Some analogues showed inhibitory activity against some glycosidases.

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Siastatin B analogues, optically active 2-(trifluoroacetamide)-3, 4, 5-trihydroxypiperidines having nitromethyl, aminomethyl and carboxyl branched groups at C-5, and (+)-(2R, 3R, 4R, 5R)-5-(aminomethyl)-3, 4, 5-trihydroxy-2-(hydroxyacetamido)piperidine have been obtained total synthetically from D-ribono-1, 4-lactone. Some analogues have inhibitory activity against some glycosidases, and (+)-(2R, 3R, 4R, 5R)-2-(trifluoroacetamido)-3, 4, 5-trihydroxypiperidine-5-carboxylic acid showed a marked inhibitory activity against β-glucuronidase.

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A series of 1β-methylcarbapenem compounds, which have a 5'-substituted-N-methylpyrrolidin-3'-ylthio group as a C-2 side chain, have been prepared and their biological properties were investigated. Substitution with a methyl group on the nitrogen atom in the C-2 side chain effectively enhanced stability to renal dehydropeptidase-I as well as introduction of methylene spacer between the aminocarbonyl group and the pyrrolidine ring of the 5'-aminocarbonylpyrrolidin-3'-ylthio group.

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Dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C₂ produced by UC 11065 were evaluated as anthelmintics. Assays used to examine these compounds included effects on the free-living nematode Caenorhabditis elegans, ability to clear target nematodes (Haemonchus contortus and Trichostrongylus colubriformis) from jirds, and clearance of Haemonchus contortus from lambs. A crude extract of UC 11065 containing dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C₂ was active against C. elegans and against H. contortus in the jird. Purified and/or synthetic samples of dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C₂ were tested in the jird model; only dioxapyrrolomycin exhibited appreciable activity against H. contortus ( ≥ 90.9% clearance at 0.33 mg/jird), while none of the compounds showed appreciable activity against T. colubriformis. Dioxapyrrolomycin cleared 99.9% of H. contortus from lambs at 12.5 mg/kg. An in vitro migration study using susceptible and closantel-resistant H. contortus showed there is cross-resistance between dioxapyrrolomycin and closantel. Dioxapyrrolomycin appears to be a narrow-spectrum anthelmintic which works through a closantel-like mode-of-action.

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D-[6-³H₃]6-Deoxy-5-ketoglucose (10) and D-[5, 6-³H₂]6-deoxyglucose (11) were incorporated into neomycins B and C using a growing culture of Streptomyces fradiae. D-[6-³H]6-Deoxy-5-ketoglucose was incorporated into neomycin, as efficiently as the well established precursor D-glucose, and was found to label exclusively the 2-deoxystreptamine ring of the antibiotic. The results strengthened the previous proposals that in the formation of 2-deoxystreptamine the G-6 hydroxyl group of D-glucose is removed prior to the cyclisation reaction. Studies using the incorporation of D-[3-³H]glucose, D-[3, 4-³H₂]glucose and D-[5-³H]glucose into neomycin followed by the degradation of the latter established that in the biosynthesis of the 2-deoxystreptamine ring the C-4 and C-5 hydrogen atoms of glucose are removed. The loss of the C-4 hydrogen atom of the glucose is attributed to the formation of a 4-keto derivative which facilitates the removal of the C-5 hydrogen atom thus setting the stage for the expulsion of the C-6 hydroxyl group. The 5, 6-olefinic intermediate formed in the process then undergoes cyclisation eventually releasing 2-deoxyinosose. The enzyme systems which participate in the conversion of D-glucose equivalent into 2-deoxyinosose may be described as 2-deoxyinosose synthase that in broad mechanistic terms resembles dehydroquinate synthase.

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