A novel, solvent extractable, antibiotic complex has been purified from the fermentation broth of an unusual member of the genus Streptosporangium. Two of the major components were isolated from the complex by alumina column chromatography. One of the components was identified as a previously reported compound, 1, 6-dihydroxyphenazine. The other component was a novel chlorine containing phenazine, 1, 6-dihydroxy-2-chlorophenazine, which exhibited broad spectrum antifungal activity in vitro against dermatophytes and Candida.

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Empedopeptin is a new antibiotic produced by Empedobacter haloabium nov. sp. (ATCC 31962). It is a water-soluble depsipeptide antibiotic containing eight amino acid residues and a C₁₄-fatty acid moiety in the molecule. Although structurally unrelated, empedopeptin and vancomycin have similar antimicrobial spectra against aerobic and anaerobic Gram-positive bacteria including antibiotic-resistant strains. Empedopeptin is highly active in vivo in mice against systemic infections of Staphylococcus aureus, Streptococcus pyogenes and Clostridium perfringens. Empedopeptin is not absorbed orally.

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Structure of a new antibiotic, empedopeptin, has been determined. It is a cyclic depsipeptide composed of two mol of D-serine and one mol each of β-hydroxytetradecanoic acid, L-arginine, D- and L-proline, L-3-hydroxyproline and D- and L-β-hydroxyaspartic acid. The sequence of these moieties was established by partial hydrolysis and mass spectral analysis of the antibiotic.

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A new inhibitor of angiotensin I converting enzyme, I5B2, was isolated from the culture broth of Actinomadura sp. No. 937ZE-1. This compound contains N-methylvaline, tyrosine and 1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid. The microorganism also produced another inhibitor, I5B1, which is identical with K-4 isolated from Actinomadura sp. as an antihypertensive agent.

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The maximum yield for the production of L-681, 110 by Streptomyces sp. MA-5038 (ATCC 31587) was observed after 5 days' incubation at 28°C and pH about 8.3. L-681, 110 was isolated from the fermentation broth by acetone extraction of the mycelia, absorption to Amberlite XAD-2 resin and two separations by thin-layer chromatography. The structure of L-681, 110 was found to consist of a sixteen-membered lactone with a new type of substitution. The inhibition of ATPase, activity against Caenorhabditis elegans and stimulation of γ-aminobutyric acid release indicate that L-681, 110 possesses some characteristics of both oligomycin and avermectin. L-681, 110 was also active against tapeworm and ticks in an in vivo assay.

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Isolation and characterization of the major components of N-acetylsporaviridins, a derivative obtained by treatment of sporaviridins with acetic anhydride in methanol were carried out. The isolation procedure as shown in Scheme 1 gave successfully six components whose molecular weights are all about 2, 200. Each component was suggested to be a glycosidic compound consisting of a macrocyclic lactone, one of viridopentaoses, a D-glucose and an N-acetyl-L-vancosamine by various spectral data.

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The structure of histargin, an inhibitor of carboxypeptidase B, produced by Streptomyces roseoviridis MF118-A5 strain, has been defined as N-[(S)-1-carboxy-4-guanidinobutyl]-N'-[(S )-1-carboxy-2-(imidazol-4-yl)ethyl]ethylenediamine, by spectral analysis and chemical synthesis.

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Teicoplanin is an antibiotic complex consisting of five closely related factors, T-A2-1, 2, 3, 4 and 5 and a more polar factor, T-A3-1. By controlled acid hydrolysis the complex is transformed into pseudoaglycones and finally into a single aglycone with consecutive removal of three sugar units. Quantitative determination of sugars obtained by degradative reactions and NMR/LC-MS studies on suitable derivatives confirmed that all the components carry one N-acyl-D-glucosamine and that at least two of them are characterized by N-decanoyl and N-undecanoyl chains on the D-glucosamine unit. The hydrolysis products still possess in vitro and in vivo activity.

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The biosynthesis of cinodine from a combination of ¹⁴C- and ¹³C-labeled precursors has been investigated. Tyrosine was shown to be incorporated efficiently into the cinnamoyl moiety and glucosamine was found to be the origin of the three carbohydrate moieties. The relationship between the substrate dose and the enrichment of the labeled antibiotic has been elucidated so that it is possible to predict both the specific activity and the yield of the antibiotic obtained from the labeled substrates.

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Thioether derivatives of tylosin and demycarosyltylosin were synthesized by MICHAEL-type addition of thiol to C-11 of the enone moiety on the aglycone. Some of tylosin derivatives were effective to macrolide resistant Staphylococcus aureus, and their in vivo activities were same or superior than that of tylosin.

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Plasmid-free strains of Streptomyces kasugaensis MB273 were isolated. In mating experiments S. kasugaensis MB273 was found to cause a lethal zygosis (pock) phenotype in a plasmid-free host. The pock-forming plasmids were identified as either pSK1^* or pSK2^* on the basis of their endonuclease cleavage-sites. The strain carrying pSK1^* was found to induce pocks on the strain bearing pSK2^*, and vice versa. The endonuclease cleavage-sites in pSK1^* and pSK2^* that were nonessential for pock formation were determined in deletion or insertion derivatives. The single sites for BelI and SalI in pSK1^* and for Bgl II in pSK2^*, respectively, could be useful for DNA cloning without destroying pock-forming ability. Protoplasts of S. kasugaensisMB273-derivatives prepared in stationary phase of mycelial growth were competent for transformation, however, regeneration frequencies decreased during this phase.

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Streptomyces kasugaensis G3 was transformed by pIJ702 DNA carrying the thiostrepton-resistance gene at a frequency of 2×10⁵ transformants/μg DNA, but it was found that the introduced pIJ702 was very unstable in this strain. This result led us to make useful vectors using the stable plasmids resident in S. kasugaensis. The Bcl I-fragment, containing the thiostrepton-resistance gene obtained from pIJ702, was inserted into the pSK1 and pSK2 plasmids isolated from S. kasugaensis. Two composite plasmids, pSK11-1 (8.0 Md) and pSK21-1 (4.8 Md), were isolated from the thiostrepton-resistant transformants of strain G3. The constructed pSK11-1 consisted of the entire pSK1 molecule and the thiostrepton-resistance gene fragment. pSK21-1 consisted of the large Bcl I-fragment of pSK2 (4.1 Md) and the same thiostrepton-resistance gene. These plasmids were stably maintained in S. kasugaensis G3. Small derivatives of these composite plasmids were prepared by restriction enzyme cleavage and self-ligation, and several unique insertion sites were also constructed in these small plasmids. By analysis of the physical maps of these plasmids, the essential regions of pSK1 and pSK2 were determined from their DNA segments to be 2.5 Md in Psk11-1 and 1.9 Md in pSK21-1. pSK21-B5, one of these plasmid vectors, showed a wide host range in the genus Streptomyces and was stable maintained in all streptomycete species tested, except S. kasugaensis M338.

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Glucosamine-6-phosphate synthetase from Escherichia coli K-12 is progressively inactivated by L-β-(2, 3-epoxycyclohexyl-4-on)alanine (anticapsin). With increasing concentrations of anticapsin the reaction exhibits rate saturation: the minimum inactivation half-time is 1.15 minutes, with a K_inact of 2.5μM. Glutamine and competitive inhibitors protect against inactivation. Fructose-6-phosphate promotes the inactivation rate. It is concluded that anticapsin is an active-site directed glutamine analog in the reaction catalyzed by glucosamine-6-phosphate synthetase.

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Incubation of the unnatural tripeptide δ-(D-α-aminoadipyl)-L-cysteinyl-D-valine (DLD-ACV) with a partially purified extract of Cephalosporium acremonium resulted in the production of deacetoxycephalosporin C. The extract contained isopenicillin N synthetase (cyclase) and deacetoxycephalosporin C synthetase (expandase) but no penicillin epimerase activity, and was incubated aerobically in the presence of the components of the cyclase and expandase reaction mixtures (Fe⁺⁺, ascorbate, dithiothreitol, α-ketoglutarate and ATP). The reaction was sensitive to penicillinase, indicating penicillin N to be an intermediate. However, when ring expansion was prevented by omission of α-ketoglutarate and ATP, no penicillin N was detected.

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Penicillin-binding proteins 1, 2 and 3 in Staphylococcus aureus were found to possess common properties. All have very strong affinities for both benzylpenicillin and imipenem (N-formimidoylthienamycin), and all have an activity which releases bound imipenem, but not bound benzylpenicillin. Lower molecular weight penicillin-binding protein 4, which has a rather weak affinity for benzylpenicillin and also weak penicillinase activity showed an extraordinarily high affinity for imipenem but no antibiotic-releasing activity.

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LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MIC50 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25μg/ml, respectively. Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5% LY121019 was as effective as 3% nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histamine-like reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog.

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A study on the pharmacokinetics of rifapentine, a new long-lasting rifamycin, has been carried out in the rat, the mouse and the rabbit. The investigation was made using either radioactive or unlabelled rifapentine and both the total ¹⁴C and the unchanged compound were assayed. In the rat, the overall evidence obtained was: (a) the oral absorption of rifapentine into central compartment, due to its poor water solubility, appears to be dose-dependent with a satisfactory oral absorption (84%) after a dose of 3mg/kg, lower (65%) after 10mg/kg; (b) the antibiotic undergoes rapid liver uptake while it diffuses into the tissue compartment more slowly, with particular affinity for the adrenals, pancreas and kidneys; concentrations higher than in plasma were also measured in the lungs; (c) elimination of rifapentine from the blood and tissue compartments suggests a non linear capacity-limited kinetics where the terminal elimination phase has monoexponential course. Terminal plasma half-life ranged between 14 and 18 hours; (d) the compound is eliminated mainly via the bile with the feces (92% of dose). In mice rifapentine shows a kinetic profile resembling that obtained in rats, whereas in rabbits is metabolized and/or eliminated much more rapidly with a half-life of only 1.8 hours.

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