A42867 is a new glycopeptide antibiotic of the ristocetin-vancomycin class active against aerobic and anaerobic Gram-positive bacteria. A42867 is produced by a strain of Nocardia nov. sp. ATCC 53492. A42867 was isolated during a screening program aimed at the discovery of new members of this glycopeptide class of antibiotics, by affinity chromatography based on an acyl-D-alanyl-D-alanine probe. The structure of A42867 was elucidated by fast atom bombardment MS, high field 2D ¹H NMR spectroscopy, and HPLC analysis of the hydrolyzed carbohydrates. A42867 differs from vancomycin in the sugar portion and in the presence of only one chlorine atom in the peptide core. Its biological activity on Gram-positive aerobic and anaerobic bacteria is similar to that of other antibiotics of this group.

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The pacidamycins are a new complex of nucleosidyl-peptide antibiotics with highly specific activity against Pseudomonas aeruginosa. They are produced by Streptomyces coemleorubidus AB 1183F-64 which was isolated from a soil sample collected at Offenburg in the FRG. The mature spore masses of the producing organism are greenish gray to blue, and the spore chains are arranged in spirals. After the structures of the pacidamycins were determined, the fermentation medium was supplemented with component amino acids. This resulted in the directed biosynthesis of several members of the complex. The overall antibiotic recovered was increased from 1 -2 mg/liter to more than 100 mg/liter through a combination of strain selection, medium manipulation and amino acid feeding experiments.

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A novel class of antibiotics was isolated from cultures of Streptomyces coeruleorubidus strain AB 1183F-64. The antimicrobial activity of the pacidamycins is selective against Pseudomonas aeruginosa. The various congeners are nucleoside peptides which differ in the terminal amino acid residues. The structures were determined using MS-MS and 2D NMR techniques.

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Pacidamycins are nucleosidyl-peptide antibiotics which have activity only against Pseudomonas aeruginosa. Their MICs for other organisms such as Enterobacteriaceae, Staphylococcus aureus, most Streptococci and other Pseudomonas species are >100μg/ml. These compounds had no activity against erythromycin-susceptible Streptococci. The MICs for Streptococcus pyogenes with constitutive- and inducible-type of macrolide-lincosamidestreptogramin resistance were 12.5 and 25 μg/ml, respectively. The MICs against P. aeruginosa ranged from 8 to 64 μg/ml. The activity of these compounds was 1 to 2-fold less in serum than broth. Time-kill curves were performed using 4 and 8 times the MIC of pacidamycin 1. It was bactericidal against P. aeruginosa (3 Iog₁₀ decrease in 4 to 6 hours). At 24 hours, resistant mutants were found in the cultures. The MICs of piperacillin and gentamicin for these mutants were the same as for the parent strain. The frequency of resistance to these compounds was <3.5×10^-6. The resistant mutants were stable after 10 transfers in antibiotic-free medium. The pacidamycins were inactive against P. aeruginosa in mouse protection tests. After a single subcutaneous injection of 25 mg/kg of pacidamycin 1, the Cmax was approximately 50 μg/ml and the serum half-life was 0.5 hour.

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Coumamidines are water-soluble basic antibiotics related to the glycocinnamoylspermidines. They are produced by a soil isolate designated Saccharopolyspora sp. AB 1167L-65. The coumamidines have broad spectrum activity and were selected in a screen for substances which inhibit Pseudomonas aeruginosa.

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Two novel, isomeric compounds, coumamidines γl and γ2 were isolated from fermentations of an actinomycete. The structures were elucidated spectroscopically using 2D NMR correlation experiments and mass spectral data. The coumamidines were found to be close structural relatives of the cinodines (LL-BM123 γl and γ2).

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The coumamidines are novel antibiotics with activity against a wide spectrum of aerobic Gram-positive and Gram-negative bacteria. All microbiological studies were performed on coumamidine γ1. The MIC₉₀s (μg/ml) of coumamidine are as follows: Staphylococcus aureus 1.0, Streptococcus pyogenes 8, Enterobacteriaceae 2.0, Pseudomonas aeruginosa 8, Campylobacter jejuni and Campylobacter coli 1, Legionella pneumophila 8, Haemophilus influenzae 0.5, Neisseria gonorrhoeae 0.5. Coumamidine had MICs ranging from 8 to > 64 for most anaerobes, except some Peptostreptococcus strains. The aminoglycoside super-sensitive strain, P. aeruginosa BMH 10, was also super-sensitive to coumamidine (MIC 0.2 ywg/ml). Coumamidine was rapidly bactericidal for S. aureus. The viable bacterial count in logarithmic phase cultures was reduced to less than 10 cfu within 2 hours after exposure to 4 times the MIC (3.12 μg/ml) of coumamidine. The frequency of resistance development was <1 × 10^-9 for Escherichia coli and S. aureus when selected at 4 and 8 times the MIC. The Cmax in mouse serum after a single subcutaneous dose of 25 mg/kg of coumamidine was 4.5 /wg/ml and t_1/2 was 1 hour. Coumamidine is stable in serum. In mouse protection tests against S. aureus NCTC 10649 the ED₅₀ was <0.6 mg/kg/day when it was administered subcutaneously at 1 and 5 hours after infection. Coumamidine was not absorbed after oral administration. The antibacterial spectrum, bactericidal activity, stability in serum and low frequency of resistance make this an interesting new class of antibiotics.

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A new antitumor antibiotic, FR900840, was isolated from a culture broth of Streptomyces strain No. 8727 as a pale yellowish prism and the molecular formula was determined to be C₇H₁₁N₃O₅. The antibiotic exhibited prominent antitumor effects on human tumor cell lines both in vitro and in vivo.

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The structure of FR900840, a new antitumor antibiotic produced by a strain of Streptomyces has been deduced as 1 on the basis of spectroscopic and chemical evidence and finally confirmed by synthesis from L-threonine and L-serine.

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FR900840 ((2S)-2-amino-2-carboxyethyl (3R)-2-diazo-3-hydroxybutyrate), a new antibiotic with antitumor activity was isolated from the fermentation broth of Streptomyces sp. No. 8727. Its antitumor activity was examined in three mouse tumor systems and ten human tumor systems. FR900840 had no clear effect on mouse ascitic tumors, P388 and L1210, and the B16 melanoma line, but had prominent antitumor effects on several human solid tumors. Its antitumor activity against A549 human lung adenocarcinoma was stronger than those of vinblastine, doxorubicin and cisplatin. These results suggest that FR900840 may become a useful prototype antitumor drug.

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A novel family of antitumor antibiotics, the calicheamicins, were isolated from the fermentation broth of Micromonospora echinospora subsp. calichensis. These antibiotics exhibited significant activity against Gram-positive and Gram-negative bacteria in vitro. Calicheamicin γ₁^I demonstrated antitumor activity against P388 leukemia and B16 melanoma in vivo.

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In the course of continued screening program for new selective inhibitors of protein kinase C (PKC), fermentation broths from over 5, 000 soil isolates were screened for their inhibitory activity of PKC. HPLC analysis of active cultures revealed that five different strains (N-71, N-115, N-126, N-128 and N-139) of Streptomyces isolated from various local soil samples were found to produce staurosporine and related compounds. Of these strains, N-126, a high producing strain, was found to produce new selective inhibitors of PKC, UCN01 and its stereoisomer, UCN-02. The pH control of fermentation resulted in an increase of the production of UCN-01 and UCN-02.

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A new inhibitor of protein kinase C (PKC), UCN-01, was isolated from the culture broth of Streptomyces sp. N-126. We have found that this strain also produces UCN-02 which is a stereoisomer of UCN-01. The inhibitors have the molecular formula C₂₈H₂₆N₄O₄ and have an indolo[2, 3-a]carbazole chromophore. Their structures have been elucidated by mass and NMR spectra. UCN-01 has been shown to inhibit PKC and protein kinase A (PKA) with IC₅₀ values of 0.0041 and 0.042 μM, respectively, and UCN-02 has been shown to inhibit PKC and PKA with IC₅₀ values of 0.062 and 0.25 μM, respectively. UCN-01 and UCN-02 also showed the cytotoxic effect on the growth of HeLa S3 cells.

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Ethyl (Z)-16-phenylhexadec-9-enoate (3), an analog of ethyl oleate (2), was synthesized and added to cultures of Streptomyces cellulosae ATCC 12625 which normally produce fungichromin (1) as the principal polyene antibiotic. These cultures showed drastic reduction of fungichromin biosynthesis but afforded four new polyene antibiotics with a truncated four carbon side chain which are designated as isochainin (11) (an isomer of chainin (10)), 14-hydroxyisochainin (12), 1'-hydroxyisochainin (13), and 1', 14-dihydroxyisochainin (14). The close correspondence of ¹³C NMR chemical shifts between these compounds and fungichromin suggests that the stereochemistry at every site is exactly analogous.

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The 3-keto derivatives of trehalose and sucrose respectively were prepared by a one-step enzymatic route using D-glucoside 3-dehydrogenase from Flavobacterium saccharophilum. Reductive amination of 3-ketotrehalose with ammonium acetate and sodium cyanoborohydride gave three compounds, 3-amino-3-deoxy-α-D-allopyranosyl α-D-glucopyranoside, 3-amino-3-deoxy-α-D-glucopyranosyl α-D-glucopyranoside 3-trehalosamine) and 3-amino-3-deoxy-α-D-mannopyranosyl α-D-glucopyranoside. From the reductive amination of 3-ketosucrose, 3-amino-3-deoxy-α-D-allopyranosyl β-D-fructofuranoside and 3-amino-3-deoxy-α-D-glucopyranosyl β-D-fructofuranoside were obtained. The antibiotic and glycohydrolase inhibitory activities of these 3-amino-3-deoxy derivatives were determined.

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Cyclosporin A (ciclosporin), a potent and clinically important immunosuppressive drug (Sandimmun), represents the main component of a group of over 25 closely related, cyclic undecapeptides produced by the fungus Tolypocladium inflatum. By feeding experiments using DL-α-allylglycine as precursor, specific incorporation in position 2 was attained leading to [Allylgly²]cyclosporin A. Exogenously supplied L-β-cyclohexylalanine results in the almost exclusive production of [MeCyclohexylala¹]cyclosporin A (replacement of methylbutenylmethylthreonine-1). D-Alanine in position 8 can be successfully substituted by D-serine. The new [D-Ser⁸] analogues of the cyclosporins A, C, D and G as well as [Allylgly²]cyclosporin A exhibit high immunosuppressive effects.

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The relationship between the chemical structure and mode of action of piperacillinanalogues (PIPC-analogues) against Pseudomonas aeruginosa was investigated. The antibacterial activities of PIPC-analogues became stronger as the chain length of the alkyl group on the N-4 position in 2, 3-dioxopiperazine when tested in constitutively β-lactamase-producing strain, but not paralleled in wild and β-lactamase-less strains. The outer membrane permeability was hardly affected by the chain length of the alkyl group at the N-4 position. The stability to β-lactamase was stronger with the increase of the number of the carbon atoms of N-4 position. In the binding-affinities to the lethal penicillin-binding proteins (PBPs), compounds PIPC (C-2), C-3 and C-4 showed lower ID₅₀ values than compounds C-1, C-6 and C-8. These results suggested that the stability to β-lactamase was the governing part for the antibacterial activity in constitutively β-lactamase-producing strain, and the binding affinity to lethal PBPs directly contributed to the antibacterial activity in wild and β-lactamase-less strains.

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We have shown that geldanamycin (GDM), an antibiotic of benzoquinoid ansamycin group, inhibits DNA replication in cultured mouse lymphoblastoma L5178Y cells. Here we report that GDM selectively inhibited the expression of c-myc gene, proto-oncogene, along with suppression of DNA replication in L5178Y cells, which are consistent with our previous results that c-myc protein promotes cellular DNA replication. The significantly enhanced inhibition by GDM of DNA replication was observed, when the antibiotic was introduced at Gl stage prior to S phase of cell cycle. The results are in favor of the prospects that GDM inhibits DNA replication mainly at time of initiation, and that c-myc protein is essential for the initiation of cellular DNA replication. Furthermore, when c-myc expression was inhibited by GDM, the expression of p53 gene, the product of which may be another DNA replication protein, was stimulated in the tumor cells. Thus, GDM should be useful to investigate the molecular mechanism of DNA replication promoted by c-myc protein and also to distinguish the function of c-myc protein from that of p53 protein in DNA replication.

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It was reported that doxorubicin inhibited virus reverse transcriptase. We have synthesized various new 14-O-acyladriamycins. The derivatives having a 14-O-benzoyl group with hydrophobic aliphatic side chains showed stronger inhibitory activity on human immunodeficiency virus reverse transcriptase and lower cytotoxicity on mouse leukemia cells.

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