Streptomyces clavuligerus produces penicillin N, several cephalosporins and the β-lactamase inhibitor clavulanic acid. The detection, isolation and properties of further metabolites of this culture, MM 21801 and MM 19290, are described. MM 21801 was identified as the antibiotic holomycin. MM 19290 was shown to be related to tunicamycin, an antibiotic complex obtained from cultures of Streptomyces lysosuperificus.

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The structure of nocamycin, a new antitumor antibiotic, has been elucidated with the aid of mass- and PMR-spectroscopic investigation of the antibiotic and its various chemical transformation products. Nocamycin is structurally related to tirandamycin

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A new compound isolated from cultures of Aspergillus candidus LINK is shown to be 3-hydroxyterphenyllin. The structure was assigned by comparing the ¹H and ¹³C nmr spectra of the metabolite and its acetate derivative with those of terphenyllin and terphenyllin
triacetate.

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A novel carbohydrate has been isolated after acidic hydrolysis of nystatin A₃, candidinin and polyfungin B and its structure established as 2, 6-dideoxy-L-ribohexopyranose.

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The chemical ionisation mass spectra of seven naturally occurring depsipeptides and some of their permethylated derivatives have been measured. The primary ionisation process involves an ester group and not an amide or other functionality. It probably occurs randomly when the molecule contains more than one ester link. Unlike electron impact mass spectra, those obtained under chemical ionisation conditions gave sequence information for all of the depsipeptides examined or their permethylated derivatives. A mechanism for the primary fragmentation is proposed.

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Neoviridogriseins, new homologues of viridogrisein, were produced with viridogrisein and griseoviridin by Streptomyces sp. P8648 which was identified as a strain of Streptomyces griseoviridus.

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Our isolate of Streptomyces griseoviridus, which produced three minor factors in addition to viridogrisein and griseoviridin, was more sensitive to the addition of L-proline than the type culture of Streptomyces griseoviridus (NRRL2427). Yield improvement of these minor factors
was attempted by the so-called controlled biosynthesis with L-proline. Addition of L-proline increased the production of neoviridogrisein II in which allo-hydroxy-D-proline in viridogrisein was replaced by D-proline.

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The effects of glucose, butyrate, and cerulenin on the formation of spiramycin I 3-hydroxyl acylase were investigated by using the cell-free extract prepared from the spiramycin-producing strain of Streptomyces ambofaciens KA-1028. Glucose induced the formation of the acylase, and this induction was remarkably repressed by butyrate. Cerulenin, on the other hand, not only canceled the repression by butyrate but also stimulated the formation of the acylase. The unsuccessful trapping of spiramycin I as an intermediate during the bioconversion from neospiramycin I to spiramycin III in the presence of cerulenin was due to the rapid acylation of spiramycin I caused by the acylase induced by cerulenin.

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Mutants have been isolated in which phosphate does not inhibit the biosynthesis of candicidin. At high phosphate concentrations, candicidin production by phosphate-deregulated mutants is still inhibited, but to a lesser extent than in the wild type. Some of these mutants are higher candicidin producers than the wild type, not only in phosphate-supplemented medium but also in non-supplemented production medium. The high candicidin production by these mutants is due to (1) a high specific rate of candicidin biosynthesis and (2) an extended production phase. None of the phosphate-deregulated mutants in which
uptake of [³²P]phosphate was measured was a phosphate-permeability mutant.

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The mutagenicity of aminoglycoside antibiotics (KM, AKM, DKB, RSM, AMK, GM, TOB) has been studied in cells of the bacteria Salmonella typhimurium and in the yeast Saccharomyces cerevisiae. The bacterial strains (AMES') monitor reverse mutation (point mutation) and the yeast strain D5 monitors mitotic crossing-over, mitotic gene conversion and point mutation. None of these antibiotics demonstrated any mutagenic activities in either the bacteria or the yeast.

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Chloramphenicol-nonproducing and plasmid-less mutants obtained previously by treatment with acriflavine still produced a small amount of chloramphenicol in a medium. To study the role of plasmid in chloramphenicol production, 70 chloramphenicol-nonproducing mutants were isolated by acriflavine treatment, high-temperature incubation, UV-irradiation or nitrosoguanidine treatment, starting from a producer (SVM2). Most of them did not produce any amount of chloramphenicol. One Mutant, SVM2-2A7 was found to produce 1-deoxychloramphenicol instead of chloramphenicol. The mutations (cpp) affecting chloramphenicol production were analyzed by crosses with a producing strain carrying the complementing auxotrophic markers. Except for the plasmid-less strains, all Cpp mutations including the 1-deoxychloramphenicol-producing mutation were mapped between met and ilv on the chromosome. Additional crosses indicated that these chromosomal cpp mutants still carried the plasmids which had a role in increasing chloramphenicol production. Therefore, it can be concluded that the structural genes for all or most steps of chloramphenicol biosynthesis including the 3-hydroxylation of p-aminophenylalanine are located between met and ilv on the chromosome of S. venezuelae and that the plasmid plays an important role in increasing the chloramphenicol production. The activity of arylamine synthetase involved in the initial step of the chloramphenicol biosynthesis was unrelated to the presence or absence of plasmid. Moreover, the presence of plasmids was not required for host
resistance to chloramphenicol.

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The synthesis and antimicrobial activity of a new semisynthetic penicillin are described. Both in vitro and in vivo, the compound shows promising antibacterial activity when compared with piperacillin and ticarcillin. High activity is shown against Pseudomonas and other Gram-negative bacteria.

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Heneicomycin is structurally similar to efrotomycin, mocimycin (kirromycin) and X-5108 (goldinomycin). Comparisons were limited because of the small supplies available. All antibiotics show the same in vitro antibacterial spectrum although some test cultures were less sensitive to efrotomycin. Heneicomycin compared favorably with efrotomycin when given subcutaneously or per os against infections with Moraxella bovis and Streptococcus pyogenes. The rapid elimination of heneicomycin observed following oral administration may account for its poor activity against a Bordetella bronchiseptica infection where efrotomycin is effective. It appears more like X-5108 than efrotomycin biologically. The disaccharide on efrotomycin may account for the difference observed.

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Rapamycin, an antifungal antibiotic produced by Streptomyces hygroscopicus showed a strong candicidal activity, which could not be reversed by sterols. It had no effect on efflux of K⁺, Pi or U.V. absorbing materials and cell permeability of Candida albicans. Thus, in its action it differs from the polyenes. Mechanism of action of rapamycin appears to be different from many known antifungal agents. In C. albicans, rapamycin at the minimum growth inhibitory concentration inhibited: 1) phosphate incorporation into nucleic acids, 2) acetate incorporation into lipids and 3) substrate respiration of amino acids. The effect on amino acid metabolism was expressed as inhibition of oxidative deamination. At low concentrations rapamycin caused degradation of P³²-labeled intracellular macromolecules. Inhibition of threonine incorporation into cell wall and leucine incorporation into cellular protein was observed at relatively higher concentrations of rapamycin. The antibiotic showed no effect on cell-free protein synthesizing systems of Escherichia coli, rat liver and C. albicans and in the mitochondrial enzyme systems. Whether the lethal action of rapamycin on C. albicans is primarily due to one of the above effects or is the result of combined effect on some of these biosynthetic parameters remains to be established.

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The fractional change in the corrected fluorescence of pimaricin or filipin in the presence of a limiting amount of sterol and a competing polyene antibiotic has been used to estimate the relative affinity of amphotericin B, nystatin, filipin, and pimaricin for stigmasterol and for cholesterol. The relative affinities for cholesterol were filipin>amphotericin B>pimaricin >nystatin, while the relative affinities for stigmasterol were filipin>pimaricin>amphotericin B>nystatin. The data indicate that pimaricin and filipin can both interact simultaneously with about 30% of the cholesterol or stigmasterol. However, the stoichiometry of filipin and pimaricin alone for cholesterol and for stigmasterol in dilute aqueous solutions is 1 : 1. In
the experiments which indicated both pimaricin and filipin interact with the same sterol molecule changes in corrected fluorescence and the absorbance spectra were monitored; and these criteria indicated that both pimaricin and filipin had interacted with the sterols. Light-scattering measurements indicate large aggregates were not formed. Although the data shows in dilute aqueous solutions the stoichiometry of filipin and/or pimaricin for sterols is 1 : 1, in more complex solutions, other combinations or interactions are indicated especially forpimaricin.

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Isocoformycin is a structural isomer of coformycin which has been demonstrated to be a potent inhibitor of adenosine deaminase. Isocoformycin showed a weaker inhibition of this enzyme than coformycin; the binding of coformycin to enzyme was irreversible, but isocoformycin inhibition was competitive with substrate. The Ki value of isocoformycin was 4.5-10×10^-5 M. Following intraperitoneal injection of isocoformycin in mice, the
adenosine deaminase activity of homogenates of several organs was determined and the following ED₅₀ values (50% inhibition doses) were observed: 29 mg/kg for thymus, 13 mg/kg for spleen, 80 mg/kg for liver and 20 mg/kg for kidney. The inhibition of adenosine deaminase in rabbit blood in vitro was also tested in comparison with coformycin.

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