The new antifungal agent nitrosofungin was isolated in high yields from a mixed culture of two organisms consisting of a bacterium of the genus Alcaligenes (UC 9152) and Streptomyces plicatus UC 8272. The bacterium produces the agent, the streptomycete enhances the production by providing a precursor or an inducer. Nitrosofungin in high concentrations inhibits a broad variety of pathogenic fungi in vitro. The agent is relatively non-toxic in small laboratory animals and high blood levels are obtained after either oral or systemic administration. Nitrosofungin is only the second N-nitrosohydroxylamine isolated from microbial sources to date. It has been identified as 2-N -nitrosohydroxylamino-1-propanol, an acidic and highly water-soluble compound.

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New antibiotics, pyrrolomycins F₁, F_2a, F_2b and F₃ were produced by Actinosporangium vitaminophilum sp. nov. when bromide ion was added to the fermentation medium. Addition of other halide ions such as chloride, iodide and fluoride ion showed no effect on pyrrolomycin production, affording polychlorinated pyrrolomycins A, B, C, D and E, but no F components. All four new antibiotics contain 2- 4 mol of bromine, and their substitutional position was determined by X-ray analysis and synthesis, supported by spectroscopic analysis. They are strongly active against Gram-positive bacteria and fungi.

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Following the previously described semisynthetic preparation of new aglycones (8S)-8-fluoroerythronolide A (I), (8S)-8-fluoroerythronolide B (II) and the monoglycoside 3-O-mycarosyl-(8S)-8-fluoroerythronolide B (III), their conversion into new fluoroerythromycins was attempted by mutational biosynthesis. The strain Streptomyces erythraeus ATCC 31772, a mutant blocked in the biosynthesis of erythromycin, was employed in the present investigation. Four new antibiotics, (8S )-8-fluoroerythromycin A (IV), (8S)-8-fluoroerythromycin B (V), (8S)-8-fluoroerythromycin C (VI) and (8S)-8-fluoroerythromycin D (VII) were successfully derived by such an approach. The result is also discussed in terms of the substrate specificity of the enzymes involved in the biosynthesis of erythromycins. The new antibiotics exhibited promising biological properties.

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From a strain of Bacillus subtilis a new antifungal peptidolipid complex of the iturin group was isolated. This antibiotic complex contained six lipophilic β-amino acids with 3-amino-14-methylpentanoic acid as the predominant component. Iturin A_L contains: 2 D-Asp, 1 L-Asp, 1 L-Glu, 1 L-Pro, 1 L-Ser, 1 D-Tyr and a mixture of 2.9% iso-C14-β-amino acid, 30.7% n-C16-β-amino acid, 15% iso-C₁₆-β-amino acid, 9% anteiso-C₁₅-β-amino acid, 35.3% iso-C₁₆-β-amino acid and 4.5% n-C₁₆-β-amino acid. The structures of the β-amino acids were determined by combined GLC/MS. FAB mass spectroscopy revealed three M+H⁺ peaks (1, 043, 1, 057, 1, 071). Iturin A_L could be resolved into six components by HPLC whose structures confirm the high amount of long chain β-amino acids.

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Streptomyces galilaeus OBB-111 and its blocked mutant were found to convert aclacinomycin B and related anthracycline glycosides of the B type to the corresponding A-type glycosides. Only the cell fraction of cultures of S. galilaeus OBB-111 was capable of catalyzing the reaction. The activity was associated with growth but dissappeared before the start of rapid
production of aclacinomycins A and B.

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Auramycinone was subjected to microbial conversion by Streptomyces coeruleorubidus ATCC 31276, a producer of baumycins. As a result, auramycinone was converted to 11-hydroxyauramycinone and 9-methyl-10-hydroxydaunomycin (feudomycin D). The results implicate auramycinone as a presumptive intermediate in the biosynthesis of 9-methyl-10-hydroxydaunomycin by S. coeruleorubidus.

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Taxonomic studies on the new species, Actinonmadura azurea are presented. A significant property of this species is the production of a new polyether antibiotic, cationomycin.

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The chemical structures of OA-6129A, B₁, B₂ and C, new carbapenem antibiotics having a pantetheinyl group at C-3 were elucidated by spectroscopic analysis and chemical transformation as presented in Fig. 1.

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Pyrrolomycins C, D and E are new members of the pyrrolomycin group of antibiotics produced by an Actinosporangium sp. The structures of pyrrolomycins C and D were determined to be 2, 3-dichloro-5-(3', 5'-dichloro-2'-hydroxybenzoyl)pyrrole and 2, 3, 4-trichloro-5-(3', 5'-dichloro-2'-hydroxybenzoyl)pyrrole, respectively, by means of spectroscopic and synthetic approaches while that of pyrrolomycin E was shown to be 5-chloro-2-(3', 5'-dichloro-2'-hydroxyphenyl)-3-nitropyrrole by spectroscopic data.

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Several derivatives of the antitumor antibiotic ravidomycin were synthesized and their anti-tumor and antimicrobial activities and mode of action were evaluated. Deacylation produced a compound with higher biological activity than the parent. Structure-activity relationship of the derivatives is discussed.

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A number of semisynthetic rifamycin derivatives modified at position 3 and/or 4, belonging to general structures 2 and 4 (see Scheme 1), have been obtained. The synthesis and the biological activities of the new compounds are described. Compounds 4p and 4qGS display very good antimycobacterial activity in mice.

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The spiropiperidylrifamycin LM 427 (4-deoxo-3, 4-[2-spiro-N-isobutyl-4-piperidyl]-(1H)-imidazo-(2, 5-dihydro)rifamycin S) displays a broad spectrum of potent antibacterial activity in vitro. In vivo it is particularly effective in the therapy of experimental tubercular infections of mice. Three schedules of treatment were employed and the best results were obtained when intermittent administrations were used (ED₅₀ of LM 427; 7 times lower than rifampicin). LM 427 is well distributed in tissues of mice and rats, with lung concentrations 10-20 times higher than plasma levels.

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Eight of nine new N-alkylaminopenicillanic acids (7a-c, e-j), prepared via efficient direct monoalkylation reactions, were found to be specific inhibitors of cephalosporinase P99 with IC₅₀≤4 mg/liter, while representative corresponding S-oxidized derivatives were less active.

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In order to improve the antibacterial activity of ampicillin, new penicillin derivatives having a 1-aryltriazole-4-carboxamide group or a 5-arylisoxazole-3-carboxamide group at the α-position of benzylpenicillin or p-hydroxybenzylpenicillin were synthesized. Some compounds in these series were found to possess high activity against Pseudomonas and other Gram-negative bacteria. In addition, structure-activity relationships, especially the effect of the hydrophobic character of the compounds on activity, were investigated.

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The production of Myxococcus xanthus antibiotic TA was stimulated by addition of alanine, serine and glycine to Casitone medium. These three amino acids served as the major biosynthetic precursors of the antibiotic. Alanine and serine were incorporated via acetate. In Casitone medium supplemented with alanine and serine, 29 to 30 of the 34 carbon atoms of antibiotic TA were derived from these two amino acids. Both carbon atoms of glycine were incorporated into antibiotic TA by a mechanism not involving acetate as an intermediate. Antibiotic TA was split into two fragments by alkaline hydrolysis followed by periodate oxidation. Radioactive alanine was incorporated into both fragments, whereas glycine was incorporated only into the smaller, polar fragment.

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The biosynthesis of the aglycones of gilvocarcins V and M has been studied with ¹³C-labeled precursors. The aglycones have been shown to be formed via the acetate pathway and a route for their biosynthesis is proposed which involves secondary addition of an alkyl group.

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Using [¹³C₂]acetate the biosynthesis of streptolydigin has been investigated. It has been demonstrated that a total of 4 acetate units are incorporated into the antibiotic, 3 into the acyl side chain and 1 into the tetramic acid portion.

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Papulacandin B inhibits glucan biosynthesis in cells of Saccharomyces cerevisiae and Candida albicans. Biological studies with a series of papulacandin derivatives showed that the short fatty acid chain and the galactose residue are not required for activity at the target site, but that they can affect penetration. On the other hand, the long fatty acid residue is essential for biological activity.

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Introduction of hybrid plasmids, which were constructed by ligation of pCR1 or pMN1 vector plasmid and SalI restriction endonuclease cleaved segments of Streptomyces cacaoi chromosome, resulted in the production of new β-lactamase and penicillin-binding protein in Escherichia coli. The β-lactamase and penicillin-binding protein were not from S. cacaoi but rather induced by the plasmids. Close relationship was observed between plasmids and penicillin-binding proteins but not with β-lactamase.

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Ten naphthalenic ansamycins were compared for their ability to kill extracellular or phagocytosed Staphylococcus aureus 502A. These included rifamycins, streptovaricins and tolypomycin Y. Although the compounds differed markedly in killing extracellular S. aureus, there was surprisingly little difference between them in assisting human leukocytes to kill phagocytosed S. aureus. In fact, when compared to rifampin, some ansamycins that were less effective in killing extracellular bacteria were more effective in killing phagocytosed bacteria. These data, together with an analysis of structure and activity, suggested that a specific transport mechanism might be involved. First considered was a vitamin K transport mechanism. Indeed warfarin, a vitamin K antagonist, blocked the ability of rifampin to kill phagocytosed S. aureus, as did the coumarins, novobiocin and coumarin-3-carboxylic acid. However, direct evidence for a vitamin K transport mechanism could not be obtained using vitamin K preparations.
The fused phenolic, bicyclic system common to all of these ansamycins was tentatively considered to be the portion necessary for phagocyte penetration.

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