During the course of our screening for squalene synthase inhibitors and Ras farnesylation inhibitors, a novel fungal culture was discovered to produce two structurally unique compounds, CP-225, 917 and CP-263, 114, as well as zaragozic acid A (squalestatin I). The two compounds are characterized by a bicyclo[4.3.1]dec-1, 6-diene core plus two extended alkyl chains. CP-225, 917 and CP-263, 114 inhibit Ras farnesyl transferase from rat brain with IC₅₀ values of 6μM and 20 μM, respectively. CP-225, 917 inhibits squalene synthase with an IC₅₀ value of 43 μM and CP-263, 114 with an IC₅₀ of 160μM. The producing organism, though not fully classified, exhibits the characteristics of a sterile Phoma species.

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In the course of our screening for new anticancer compounds produced by marine bacteria, we found that a new genus marine bacterium Pelagiobacter variabilis produced new phenazine antibiotics, pelagiomicins A, B and C. Those compounds were labile in water and alcohols. The absolute structure of the main component; pelagiomicin A, and the structures of the minor ones were determined from the spectroscopic data and by synthesis. Pelagiomicin A exhibits activity against Gram-positive and -negative bacteria and antitumor activity in vitro and in vivo.

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A novel metabolite, benesudon, possessing antibacterial, antifungal, cytotoxic and phytotoxic activities, was isolated from submerged cultures of the ascomycete Mollisia benesuada. Benesudon contains a reactive α-methyleneketone moiety which is believed to be responsible for its antibiotic activities, it reacts with cysteine and the reaction products are devoid of biological activities. Benesudon is the first secondary metabolite described from Mollisia benesuada, and its structure was determined by spectroscopic techniques.

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New benz[a]anthraquinone antibiotics (brasiliquinones A, B and C) with an ethyl group at C-3 were isolated. The producer was identified as Nocardia brasiliensis. The antibiotics were active against Gram-positive bacteria including Mycobacterium sp., but not active against Gram-negative bacteria or fungi. They were also active against multiple drug-resistant P388/ADR tumor cells.

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The development of a screen targeted to antibiotics which bind elongation factor Tu (EF-Tu) is described. The method was based on selection of antimicrobial activities which were antagonized by exogenous EF-Tu. Kirromycin, a known inhibitor of EF-Tu, was positive in this screen. Among 47, 000 microorganisms screened, several producers of kirromycin-type antibiotics were detected and the novel antibiotics GE2270 and GE37468 were discovered. These thiopeptide molecules constitute, along with amithiamycin, a novel class of antibiotics acting on EF-Tu.

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A genomic DNA library from the enomycin (ENM) producer, Streptomyces mauvecolor, was screened for the ENM structural gene (enm) by use of a segment of the phenomycin gene (phm) as the probe, and a plasmid, pEN1, was constructed. By primer-walking along the insert, a 573 bp DNA sequence that contain an ORE corresponding to preENM was determined. The deduced amino acid composition of ENM was close to that previously reported (MIZUNO, S.; K. NITTA & H. UMEZAWA: Mode of action of enomycin, an antitumor antibiotic of high molecular weight. I. Inhibition of protein synthesis. J. Biochem. 61: 373-381, 1967). The producer cells expressed enm during an ENM-productive fermentation. An enm-expression plasmid, pENE 1, was constructed, with which E. coli AD202 was transformed. The transformant produced a fusion protein consisting of glutathione-S-transferase (GST) and ENM. The genetically engineered ENM (rENM) inhibited the growth of Hela cells in vitro. Comparison of the base sequence spanning enm with that spanning phm showed that the structural genes were conserved more extensively than were the flanking regions, though the genes were unlikely to be essential to the lives of the producers.

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The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-α-L-cladinosyl moiety as a neutral sugar are described. These potent novel derivatives have been efficiently synthesized avoiding glycosylations. Two hydroxyl groups in mycarose of the tri-(tert-butyldimethylsilyl) ether intermediate were successively alkylated. Sequential deprotections of silyl groups afforded 4-O-alkyl-L-cladinose analogues and 3, 4-di-O-alkyl-L-mycarose analogues of leucomycin V. Some 4-O-alkyl-L-cladinose analogues exhibited potent antibacterial activities. The most active derivative, 3"-O-methyl-4"-O-(3-methylbutyl)leucomycin V, showed improved metabolic stability in rat plasma in vitro and extremely high concentrations in serum after oral administrations in mice and in hamsters.

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The filamentous fungus Aspergillus nidulans is able to grow on phenylacetic acid (PhAc) as the sole carbon source and has a highly specific phenylacetic acid transport system mediating the uptake of this aromatic compound. This transport system is also able to transport some phenoxyacetic acid (PhOAc), although less efficiently. Maximal uptake rates were observed at 37°C in 50 mM phosphate buffer (pH 7.0). Under these conditions, uptake was linear for at least 1 minute, with Km values for PhAc and PhOAc of 74 and 425 μM, respectively. The PhAc transport system is strongly induced by PhAc and, to a lesser extent by PhOAc and other phenyl derivatives. The utilization of glucose (and other sugars), glycerol or acetate results in a substantially reduced uptake. This negative effect caused by certain carbon sources is independent of the creA gene, the regulatory gene mediating carbon catabolite repression. Negative regulation by acetate is prevented by a loss-of-function mutation in the gene encoding acetyl-CoA synthetase, strongly suggesting that this regulation is mediated by the intracellular pool of acetyl-CoA.

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The direct stimulation by neutrophil-infectious bacteria induces an increase in the production of reactive oxygen species which is an important host defense mechanism. Antibiotics that enter rapidly and are concentrated in neutrophils, can stimulate or damage this function. In this study, an in vitro evaluation has been made of the macrolide, dirithromycin, and its active metabolite, erythromycylamine, on the superoxide anion generation by neutrophils in three systems of stimulation: the oligopeptide fMLP, an analogue of bacterial chemotactic factors; the phorbol ester PMA, a direct activator of protein kinase C; and a bacteria strain, Staphylococcus aureus. It has been demonstrated that dirithromycin, at therapeutic plasma concentrations, and its active metabolite have a significant pro-oxidant effect on the two systems: fMLP and bacteria. This effect is greater for dirithromycin than that for erythromycylamine. At higher non-therapeutic concentrations, these substances decrease superoxide generation in the three systems. The effects of these two agents seem to be the result of an intracellular mechanism resulting in the intervention of the oxidative metabolism of neutrophils since no effect was found in the cell-free systems. Therefore, this in vitro study suggests that at therapeutic concentrations, dirithromycin and erythromycylamine could benefit therapy by stimulation of the oxidative metabolism of neutrophils.

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Chloropeptins I and II, which are gp120-CD4 binding inhibitors, were isolated as pale yellow-brown powders from the mycelia of a soil actinomycete, Streptomyces sp. WK-3419. Their physico-chemical properties showed that they are chlorinated pep tides. Chloropeptin I (C₆₁H₄₅N₇O₁₅Cl₆) is a novel compound, but chloropeptin II was identified as complestatin. Both compounds inhibited gp120-CD4 binding (IC₅₀: 1.3 and 2.0 μM, respectively), the cytopathic effect of HIV in MT-4 cells (EC₅₀: 1.6 and 1.7 μM, respectively) and syncytium formation in co-cultured HIV-1-infected and uninfected MOLT-4 cells (IC₅₀: 0.5 and 1.1 μM, respectively). Chloropeptin I was synergistic in the inhibition of the cytopathic effect when combined with other anti-HIV drugs such as zidovudine (AZT), didanosine (ddl), zalcitabine (ddC) and nevirapine.

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The structure of chloropeptin I, a gp120-CD4 binding inhibitor having a potent anti-HIV activity, was elucidated by ¹H and ¹³C NMR experiments and chemical degradation. It is a peptide antibiotic consisting of six aryl amino acids residues and an α-oxo aryl acid some of which have chlorine atoms.

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The replacement of amino acids 1 and 3 of glycopeptide antibiotics (dalbaheptides) with new amino acids or other chemical entities suitable to interact with both glycopeptide-resistant (D-Ala-D-Lactate) and susceptible (D-Ala-D-Ala) targets is one of the chemical strategies currently followed to pursue activity against highly glycopeptide-resistant Van A enterococci while maintaining activity against glycopeptide-susceptible Gram-positive bacteria, particularly methicillin-resistant staphylococci. As a preliminary approach, the substitution of amino acid 1 of deglucoteicoplanin (TD) with D-lysine or D-methylleucine and of its amino acid 3 with L-phenylalanine or L-lysine was investigated.
In this paper, the synthesis and in vitro antibacterial activities of first non-natural dalbaheptide methyl ester aglycons MDL 63, 166 (D-Lys¹-Phe³-TD-DHP-Me), MDL 64, 945 (D-Lys¹-Lys³-TD-DHP-Me), and MDL 64, 468 (D-MeLeu¹-Lys³-TD-DHP-Me) are described. These compounds, which were obtained from intermediate TD-derived tetrapeptide methyl ester (TDTP-Me) according to a 9-step overall procedure, had excellent anti-staphylococcal activity. The most active derivative against staphylococci, MDL 64, 945 (MIC: 0.063 μg/ml for S. aureus, S. epidermidis and S. haemolyticus) was inactive against VanA enterococci, while MDL 63, 166 and MDL 64, 468 were somewhat active against VanA strains of E. faecalis; MDL 64, 468 was also moderately active against one VanA isolate of E. faecium and had marginal activity as TD against E. coll.

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