A new member of the aurodox family of antibiotics, A83016F, has been isolated from an unidentified actionmycete designated A83016. The structure and relative stereochemistry of A83016F were elucidated by NMR examination of the parent compound and its diacetate derivative. A83016F exhibits only weak antimicrobial activity.

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A novel polycyclic xanthone, Sch 42137, related to the albofungin family of compounds was isolated from culture broth. Its structure was determined by detailed spectroscopic studies and comparison of circular dichroic studies to related compounds albofungin and simaomicin. Sch 42137 exhibited MIC values < 0.125 μg/ml against yeasts and dermatophytes. Details are presented herein.

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10'-Desmethoxystreptonigrin, a novel analog of streptonigrin produced by Streptomyces albus, was discovered in a screen for inhibitors of farnesylation of RAS p²¹ protein. The compound was isolated from the fermentation broth and its structure determined. It is markedly cytotoxic to several human tumor cell lines and also exhibits potent broad-spectrum antibacterial activity.

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AB3217-A, a novel anti-mite substance, was isolated from the fermentation broth of a streptomycete strain. The strain was isolated from a soil collected at Kita-azumi, Nagano Prefecture, Japan, and identified as Streptomyces platensis AB3217.
AB3217-A was purified by Amberlite IR120B, Diaion HP-20 and CM-Sephadex C-25 column chromatographies. The molecular formula was determined as C₁₇H₂₃NO₇ by elemental analysis, MS and ¹³C NMR spectroscopy. The structure of AB3217-A was determined to be (1R, 3S, 4S, -7R, 8R, 11R, 12S, 13R)-4, 12, 13-trihydroxy-8-(4-methoxyphenyl)-6-aza-2, 9, 14-trioxatncyclo-[9.2.1.0^{3, 7}]tetradecane by spectroscopic analysis and X-ray crystallographic analysis. The molecule of AB3217-A has unique structure that deacetylanisomycin and β-D-xylofuranose linked through glycosidic bond and ether bond resulting in the formation of nine-membered ring.
AB3217-A showed marked activity against the two spotted spider mite, Tetranychus urticae.

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The effect of utilizable carbon sources on the production of gentamicin by Micromonospora purpurea has been studied. High D-glucose and D-xylose concentrations (40 mg/ml), exerted a strong and permanent negative action on antibiotic formation. On the other hand, similar concentrations of D-fructose, D-mannose, maltose and starch caused no effect. The glucose action is seen only if added during the logarithmic growth phase; moreover, the sugar needs to be metabolized to show its negative effect.

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The chemical structure of a unique polyenic antibiotic enacyloxin IIa (former name: fr. 2) produced by Frateuria (formerly Gluconobacter) sp. W-315 has been determined by extensive spectroscopic studies, in particular by NMR spectral analysis. It has a novel non-lactonic structure involving 3, 4-dihydroxycyclohexanecarboxylic acid with a chlorine-containing polyenic and polyhydroxy acyl side chain attached as an ester to the 3-hydroxyl substituent of the acid.

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New antibiotics enacyloxins (ENXs) are a family of non-lactonic polyene antibiotics produced by Frateuria sp. W-315. For the production of antibiotics, we had to employ two-step fermentations, the first is the production of spent medium of Neurospora crassa and the second is the production of antibiotics by Frateuria. To simplify the production of antibiotics, systematic analyses have been done on the spent medium, and factors which affect the production of antibiotics characterized. From the above results, we constructed a new medium for antibiotic production. Moreover, we could get a new antibiotic named enacyloxin IIIa (1), C₃₃H₄₈O₁₁NCl (m/z 669). 1 was deduced to be one of the congeners of enacyloxins because it was similar to ENX IIa or ENX IVa both in biological and physico-chemical properties. Chlorine of 1 could be replaced by bromine, biosynthetically, and the resultant bromine-containing antibiotic also showed an antibacterial activity comparable to 1.

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As a part of our research on the synthesis of cephalosporins bearing condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus, we describe herein the synthesis of 7β-[2-(2-amino-5-halogeno-, methylthio-, methylsulfinyl-, methylsulfonyl- and sulfothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]cephalosporins and their antibacterial activity. Among the compounds prepared, 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(imidazo[1, 5-a]-pyridinium-1-yl)methyl-3-cephem-4-carboxylate (14) showed good antibacterial activity against both Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRS A) and Pseudomonas aeruginosa, whereas the antibacterial activity against other Gram-negative bacteria was a slightly lower than that of 7β-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(imidazo[1, 2-a]pyridinium (I-1) and imidazo[1, 5-a]pyridinium (I-4)-1-yl)methyl-3-cephem-4-carboxylates.

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A series of new penem compounds with a C-2 side chain consisting of a pyrrolidin-3'-ylthio group substituted with various aminocarbonyl groups at the C-5' position have been prepared. Antibacterial activity, stability to renal dehydropeptidase-I and affinity to penicillin-binding proteins of these compounds were investigated and compared with the corresponding carbapenem compounds.

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The aminothiazolyl-cephalosporin RU 29 246 is the active metabolite of the prodrugpivaloyl-oxyethyl-ester HR 916. RU 29 246 in vitro activity includes a wide range of clinically relevant bacterial pathogens. Against methicillin-sensitive Staphylococci RU 29 246 (MIC₉₀ of 0.25-2μg/ml) was clearly more active than cefaclor, cefuroxime, cefpodoxime, cefixime and ceftibuten, but slightly less active than cefdinir. RU 29 246 inhibited hemolytic Streptococci of the serogroups A, B, C and G as well as penicillin-sensitive Streptococcus pneumoniae at concentrations similar to cefdinir, cefpodoxime and cefuroxime (MIC₉₀≤0.13μg/ml), but less than the other oral cephalosporins investigated (cefixime, cefaclor and ceftibuten). MIC₉₀s of RU 29 246 against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella spp., Shigella spp., Proteus mirabilis and Haemophilus influenzae were ≤0.5μg/ml. Only RU 29 246 and cefdinir demonstrated moderate activity against Acinetobacter baumannii (MIC₉₀≥4μg/ml). Most strains of Pseudomonas spp., Serratia marcescens, Enterobacter spp., Hafnia alvei and Bacteroides spp. were resistant to RU 29 246.
RU 29 246 killed Escherichia coli and Staphylococcus aureus at a rate of 99% to 99.9% at concentrations of two times MIC.
The pH value of the medium (range 5.5 to 8.5) and the inoculum size (range 10⁵ to 10⁷ cfu/ml) had no or only low influence on the antibacterial activity of RU 29 246.
RU 29 246 is a broad spectrum cephalosporin including in its activity both Gram-positive and Gram-negative pathogens and therefore-depending on the bioavailability of its prodrug-looks promising as to its therapeutic perspective.

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The aminothiazolyl-cephalosporin RU 29 246, the active metabolite of the prodrug-ester HR 916, is active against strains producing the widespread plasmid-encoded TEM-1, TEM-2 and SHV-1 β-lactamases. Except for TEM-7 the activity of RU 29 246 against strains producing extended broad spectrum β-lactamases (TEM-3, TEM-5, TEM-6, SHV-2, SHV-4, SHV-5, CMY-1, CTX-M), however, is low. Relative hydrolysis rates of RU 29 246 are comparable with those of cefpodoxime, the active metabolite of CS-807, and are extremely low for the TEM-1 and SHV-1 β-lactamases. The compound demonstrates remarkable inhibitory activity against the chromosomal β-lactamase of Enterobacter cloacae P99. In the presence of 1.7μM this enzyme loses 50% of its activity. At concentrations of 0.43, 0.003 and 0.01 μg/ml the compound binds preferentially to the penicillin-binding protein (PBP) 3 of Escherichia coli K12, to the PBPs 2x and 3 of Streptococcus pneumoniae R6 and to PBP 1 of Staphylococcus aureus SG 511, respectively.

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A series of O-methylazithromycin derivatives have been synthesized and their antibacterial activities were compared with those of azithromycin (1). O-Methylation of 1 proceeded stepwise by the two main pathways beginning at the C-6 and C-11 hydroxyl groups, individually. Among O-methyl derivatives, 6-O-methylazithromycin A (11) was slightly less active than 1. The methylation of the secondary hydroxyl group at the C-11 position resulted surprisingly in an increase of their in vitro activity. The antibacterial activities of novel azalides decreased with increasing the number of the methyl groups introduced.

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The synthesis and biological properties of new 3-phenoxymethylcephalosporins (1) are described. These compounds exhibited good antibacterial activity against Gram-positive and Gram-negative bacteria.

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Transfer of imipenem resistance in Bacteroides fragilis was studied. Clinical isolate B. fragilis 10-73 was highly resistant to imipenem. Imipenem resistance was transferred from 10-73 to B. fragilis strain TM4000 at a frequency of 10^-6/input recipient by a filter mating technique. The resistance could also be retransferred. B. fragilis 10-73 and both primary and secondary transcipients produced an imipenem-hydrolyzing metallo-β-lactamase. Acquisition of imipenem resistance correlated with the appearance of plasmid DNA with a size (ca. 13.6kb) similar to that of the donor strain. TM4000 transformed by electroporation with purified DNA of the 13.6-kb plasmid pBFUK1 produced the metallo-β-lactamase and was resistant to imipenem. Transfer was resistant to DNase treatment and no transfer was seen with a sterile filtrate of the donor culture. It is suggested that gene transfer in B. fragilis has the properties of a conjugation system rather than those of transformation or transduction.

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The mechanism of lipid peroxidation catalyzed by bleomycin (BLM)-iron (Fe) complexes has been studied in vitro using sodium linoleate as a substrate. BLM-Fe(II)-O₂. and BLM-Fe(III) complexes catalyze lipid peroxidation concomitantly with singlet oxygen evolution. The results from spin trapping methods and gas chromatography-mass spectroscopy (GCMS) analyses suggest that the initial step of lipid peroxidation catalyzed by BLM-Fe complexes is similar to that of soybean lipoxygenase, viz., hydrogen abstration. However, another mechanism might be concerned in the case of BLM-Fe(II)-O₂ complex. BLM-Fe complexes are also capable of enhancing singlet oxygen evolution from the hydrogen peroxide (H₂O₂)-hypochlorite (OC1^-) system.

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We examined the effect of various polyether antibiotics on colchicine resistance in multidrug-resistant KB-C4 cells which exhibit about 4, 000-fold resistance to colchicine. As a result, 4 out of 14 polyether antibiotics were found to reverse colchicine resistance. Among them, laidlomycin was the most potent. It potentiated colchicine cytotoxicity on KB-C4 cells about 700-fold at 1μg/ml. Degree of potentiation was calculated by dividing of the IC₅₀ value of colchicine in the absence of a polyether antibiotic by the IC₅₀ value of colchicine in the presence of the polyether antibiotic. Monensin, dianemycin, and leuseramycin at 3μg/ml also potentiated the cytotoxicity, about 100-fold. We previously reported that inostamycin is a potent chemosensitizer in KB-C4 cells. Although lysocellin has a structure very similar to that of inostamycin, it didn't reverse colchicine resistance. It slightly increased [³H]vinblastine accumulation in KB-C4 cells and weakly inhibited the [³H]vinblastine binding to KB-C4 plasma membranes.

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The biosynthesis of antibiotic 1233A (F-244) was studied by feeding ¹³C-labeled precursors to the producing organism, Scopulariopsis sp. F-244. ¹³C NMR spectroscopy established that 1233A is derived from 4 methionines and 7 acetates. Seven acetates are condensed to form a hexaketide and 4 methyl residues from methionine are introduced into the main skeleton. The β-lactone is derived from the α-carboxylic acid of the hexaketide. Since methionine was efficiently incorporated into 1233A, radiolabeled 1233A was prepared biosynthetically by feeding [¹⁴C]methionine to the producer. As a result, [¹⁴C]1233A was obtained with high specific radioactivity (27.2 μCi/μmiol).

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