GERI-BP001 compounds, new inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT), were isolated from a culture broth of Aspergillus fumigatus F37 by acetone extraction, EtOAc extraction, SiO₂ column chromatography, and reverse phase HPLC. GERI-BP001 M, A, and B inhibit ACAT activity in an enzyme assay system using rat liver microsomes by 50% at concentrations of 42, 94, and 40 μM, respectively.

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FR901537 is a new aromatase inhibitor produced by a bacterium Bacillus sp. No. 3072. Structural studies of FR901537 suggested that it was a novel naphthol derivative having pantetheine in its structure.
FR901537 showed a potent inhibitory activity against aromatase from human placenta or rat ovary, but did not inhibit the activity of 11β-hydroxylase from bovine adrenal cortex. Lineweaver-Burk plot analysis revealed that FR901537 is a competitive inhibitor.

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The pharmacological and antitumor effects of FR901537, a new aromatase inhibitor, isolated from Bacillus sp. No. 3072, were studied. Treatment for four consecutive days with FR901537 inhibited the androstenedione-induced increase in the uterus weight in immature rats. FR901537 had no effect on the uterus, adrenal glands, ovary or pituitary weights in mature rats following 14 days of treatment. The antitumor activity of FR901537 on 7, 12-dimethylbenz(a)anthracene-induced mammary tumors was studied in ovariectomized, testosterone propionate (TP)-treated rats as a postmenopausal tumor model. Ovariectomy caused the regression of the mammary tumors and the growth of tumors was remarkably stimulated following TP treatment. Further, in the rats treated with FR901537 and TP, the TP-induced tumor growth was significantly inhibited by FR901537. These results suggest that FR901537 is a promising drug in the treatment of estrogen-dependent mammary tumors in postmenopausal women.

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In the course of screening for microbial products with antitumor activity, new antitumor agents, clecarmycins, were isolated from culture broth of Streptomyces sp. DO-114. The antibiotics were produced in a fermentation medium supplemented with a highly porous polymer resin which adsorbs antibiotics and results in a increase of titer. Active materials were separated from the polymer resin by solvent extraction procedure and two components named clecarmycin Al and C were isolated by silica gel column chromatography. These were active against bacteria, and showed antiproliferative activities against human HeLa S3 cells. Clecarmycins exhibited antitumor activity against leukemia P388 and sarcoma 180 in mice.

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AL072 is a potent anti-Legionella antibiotic produced by Streptomyces strain AL91. The compound was isolated from the fermentation broth with 1 volume of isopropyl alcohol, followed by an ethyl acetate extraction and subsequent concentration under reduced pressure. Purification was performed on an octadecyl silica gel column followed by preparative HPLC. AL072 purified as mentioned above showed extremely specific activity only towards Legionella pneumophila. No antibacterial activity against any other bacteria tested was demonstrable. Its molecular weight was determined by FAB-MS (m/z 648) and the compound was identified as a novel 1, 3-diacyl glycerol with the molecular formula C₄₁H₇₆O₅. One of the two acyl groups is linoleyl and the other is 3, 5-dimethyl octadecanoyl.

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GE37468 A is a new thiazolyl peptide antibiotic obtained by fermentation of Streptomyces sp. strain ATCC 55365. It inhibits bacterial protein synthesis by acting on elongation factor Tu and is structurally and functionally related to the GE2270 class of EF-Tu inhibitors. It is active in vitro against Gram-positive bacteria and Bacteroides fragilis, and protects mice against Staphylococcus aureus infection.

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A new antibiotic, ripostatin, was isolated from the culture supernatant of the myxobacterium, Sorangium cellulosum strain So ce377. It is a macrocyclic lactone carbonic acid containing an unsubstituted phenyl ring in a side chain. The antibiotic acts especially on Staphylococcus aureus, but seems not to penetrate most bacteria.
The MIC values are in the range of 1 μg/ml. Ripostatin is an inhibitor of eubacterial RNA polymerase. It interferes with the initiation of RNA synthesis.

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Eight new components of terpendoles E to L were isolated and characterized from the culture broth of Albophoma yamanashiensis using a different production medium. All the structures were elucidated by spectroscopic analyses including various NMR experiments, indicating that all the terpendoles have the same indoloditerpene core as terpendoles A to D. Terpendoles J, K and L showed the moderate inhibition against acyl-CoA: cholesterol acyltransferase (ACAT) activity with IC₅₀ values of 38.8, 38.0 and.32.4μM in rat liver microsomes, respectively. But terpendoles E-I showed weak activities (IC₅₀ 145-388μM).

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The clinically important glycopeptide antibiotic vancomycin binds to bacterial cell wall peptides of Gram-positive bacteria which terminate in -Lys-D-Ala-D-Ala, thereby inhibiting cell wall synthesis resulting in cell death. We have removed the N-terminal leucine residue of vancomycin by an Edman degradation and acylated the exposed amino group of residue 2 with N-Me-Gly, N-Me-D-Ala, acetyl, butyl, and isohexyl groups to generate novel vancomycin analogues. The binding of vancomycin and these vancomycin analogues to the bacterial cell wall analogue di-N-Ac-L-Lys-D-Ala-D-Ala (DALAA) was studied by NMR techniques and UV spectroscopy. The effects that these structural modifications of the carboxylate binding pocket of vancomycin have on the antibiotic-DALAA recognition process show that a cooperative effect between non-polar and ionic forces appears to be partly responsible for the highly efficient sequestering of the DALAA C-terminal carboxylate from aqueous solution.

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In two pandavir (nigericin) producing strains, Streptomyces hygroscopicus 155 and Streptomyces albogriseolus 444, an enzyme activity was detected leading to inactivation of the antibiotic in the presence of ATP-Na₂. Apparently, the observed inactivation is specific for the antibiotic produced by these strains. The nigericin producing strains were also found to be less permeable to pandavir than their non-producing variants.

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The ability of strains of Bacillus, Staphylococcus, Pseudomonas, and Escherichia coli to inactivate rifampicin was tested. Most Bacillus strains were found to inactivate rifampicin. Two modes of inactivation were identified; one was phosphorylation and the other involved decolorization. Presence or absence of either mechanism appeared unrelated to the phylogenetic relatedness of strains. None of the other organisms could inactivate this antibiotic.

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A novel Cyclodepsipeptide of fungal origin, PF1022A, recently was reported to have anthelmintic activity. To supplement published reports and determine potential utility of PF1022A as a ruminant anthelmintic, the compound was examined in in vitro and in vivo models. Assays used measured motility of Haemonchus contortus (intrinsic drug potency), ATP levels (parasite death), and activity against H. contortus, Ostertagia ostertagi, and Trichostrongylus colubriformis in the jird (spectrum, potency, and efficacy by various routes). The potency of PF1022A in reducing motility is greater than commercial anthelmintics. Examination of ATP levels in PF1022A-paralyzed H. contortus indicates that worms are not killed, suggesting the compound acts as a neurotoxin in nematodes. In the jird, PF1022A has activity orally against each of the parasites studied and at doses comparable to all commercial anthelmintics, except the macrocyclic lactones which are more potent. Unfortunately, for some nematode species, parenteral delivery is ineffective at realistic doses.

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The anti-fungal antibiotic, radicicol, produced in the culture broth of Neocosmospora tenuicristata, was found to induce differentiation of HL-60 cells into macrophages from the following evidence: (1) it caused morphological changes into macrophage-like cells, (2) induced NBT (Nitrobluetetrazolium) reduction activity, (3) induced phagocytosis, and (4) induced α-naphthyl acetate esterase activity. The concentration of radicicol required to differentiate HL-60 cells is 50-100ng/ml, and the incubation time required for commitment of differentiation is 16 hours. Flow cytometry analysis indicated that radicicol blocks the cell cycle of HL-60 cells at the Gl and G2 sites. In addition, radicicol induced reversal of the transformed phenotype of ras-transformed NIH3T3 cells (DT cells) at 25ng/ml.

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Microbial oxidation of milbemycin A₄ at the C-25 ethyl group was performed. Milbemycin A₄ was converted to 31- and 32-hydroxy derivatives by Cirdnella umbellata SANK 44272 along with 24- and 30-hydroxy derivatives. Related compounds, 5-ketomilbemycin A₄ 5-oxime and 13β-fluoromilbemycin A₄ were similarly converted to the hydroxylated compounds by this microorganism. Absidia cylindrospora SANK 31472 converted milbemycin A₄ to the corresponding 32-oic acid, 24-hydroxy derivative and a few oxygenated compounds including at the C-25 ethyl group.

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The planar structure of aculeximycin (1) produced by Streptosporangium albidum has been determined by spectral methods and chemical degradations such as 1, 8-diazabicyclo[5, 4, 0]undec-7-ene (DBU)-methanol reaction, ozonolysis, and periodative oxidation. The antibiotic consists of a 30-membered polyhydroxy lactone ring, an α, β-unsaturated ester group, an intramolecular hemiketal, an oligosaccharide (aculexitriose), a neutral sugar and an amino sugar. The structure of aculeximycin is closely related to those of sporaviridins produced by Streptosporangium viridogriseum. We consider that aculeximycin and sporaviridins belong to a new class of macrolide antibiotics, which is different from the polyol macrolides produced by Streptomyces.

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Aculeximycin (1) produced by Streptosporangium albidum possesses a 30-membered polyhydroxy macrocyclic lactone and five sugars including aculexitriose. We have described the determination of the planar structure of N-diacetylated aculeximycin (2) using degradation products, which were obtained by DBU-methanol treatment, ozonolysis and periodative oxidation. In order to determine the relative and absolute configurations of aculeximycin, first, the relative and absolute configurations of the degradation products 10, 11, 12 and 13 were determined. Rychnovsky's method was very useful to determine the relative configurations of these degradation products, and CD exciton chirality and the modified Mosher's methods were applied to determine their absolute configurations. From these results, fourteen out of the twenty asymmetric centers in aculeximycin were determined to be 5S, 17R, 20S, 21R, 23R, 24R, 29S, 30R, 31S, 34R, 35S, 36S and 37R. The absolute configurations at C-14 and C-15 on the hemiketal ring were confirmed using 12 obtained by the partial glycol bond cleavage of 9. Absolute configurations of the remaining asymmetric centers were determined by spectral analysis of 15 and NOE experiment on 1. From these results, the absolute configuration of 1 was determined to be 5S, 7R, 10S, 11R, 14R, 15S, 17R, 19R, 20S, 21R, 23R, 24R, 25S, 29S, 30R, 31S, 34R, 35S, 36S and 37R.

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New compounds, structurally related to the potent protein kinase C inhibitor staurosporine, and substituted on the imide nitrogen with a functional group bearing a labile hydrogen (hydroxymethyl, amino, hydroxy), were synthesized. Their in vitro inhibitory potencies towards protein kinase C and protein kinase A showed that N-hydroxymethyl and N-hydroxy substitution, unlike alkyl substitution, can provide efficient protein kinase C inhibitors. The antimicrobial activities of these new compounds against Streptomyces chartreusis and Streptomyces griseus, Bacillus cereus, Escherichia coli, Candida albicans and Botrytis cinerea were examined. They proved to be inactive against E. coli and two fungi. The results suggest that there is no link between in vitro inhibition of protein kinase C and inhibition of growth and sporulation of the two Streptomyces tested. Unlike indolocarbazole maleimides, bis-indole maleimides are active against the two Streptomyces species.

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A series of amide derivatives of natural glycopeptide A-40, 926 (A), its 6^B-methyl ester (MA) and 6^B-decarboxy-6^B-hydroxymethyl derivative (RA) were prepared with the aim of obtaining activity against glycopeptide-resistant enterococci.
These compounds are structurally related to a class of amides of 34-de(acetylglucosaminyl)-34-deoxy teicoplanin which showed interesting activity against strains of Enterococcus faecalis and E. faecium highly resistant to both vancomycin and teicoplanin. Among them, RA-amides MDL 63, 246 and MDL 63, 042 were the most active derivatives against several Gram-positive bacteria, including VanB and VanC enterococci, and were moderately active (MIC range 0.5-64μg/ml) against strains of Enterococcus for which vancomycin and teicoplanin MICs were ≥128μg/ml.
The chemical rationale and the synthesis of these new series of glycopeptide derivatives are described. Preliminary in vitro data are reported and structure-activity relationships are discussed.

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