Showing papers on "Thienamycin published in 1986"
TL;DR: An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate.
Abstract: An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate. THX was subsequently identified as one of the four possible stereoisomers of 4-fluorothreonine. Inorganic fluoride or any one of a number of organofluorine compounds can be used as precursors of 4-fluorothreonine. In addition, 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions. The in vitro antibacterial spectrum of 4-fluorothreonine is also presented.
148 citations
TL;DR: Synthese de l'ester methyle-1 de l"acide amino-2 hydroxy-4 pentanedicarboxylique-1,3 (precurseur de la (+) thienamycine) as discussed by the authors
Abstract: Synthese de l'ester methyle-1 de l'acide amino-2 hydroxy-4 pentanedicarboxylique-1,3 (precurseur de la (+) thienamycine)
55 citations
53 citations
TL;DR: In this article, the configurationally stable aldehyde was transformed to enantiomerically pure β-lactams by Oxidative cleavage of crotonate imide imide aldol adduct.
45 citations
29 citations
TL;DR: The lithium enolate of benzyl β-phenyldimethylsilylbutanoate reacts with aldol to give β-lactam, a known precursor of thienamycin this article.
Abstract: The lithium enolate (1) of benzyl β-phenyldimethylsilylbutanoate reacts with β-phenyldimethylsilylpropionaldehyde (2) to give, with high diastereoselectivity, the aldol product (3), which is converted into the β-lactam (7), a known precursor of thienamycin.
29 citations
TL;DR: Conventional in vitro tests were not uniformly predictive for in vivo (murine) chemotherapeutic efficacy and vancomycin and fosfomycin proved as efficacious as penicillin G and imipenem in an experimental mode of murine gas gangrene.
Abstract: Penicillin G and imipenem (N-formimidoyl thienamycin) in vitro were the most active of twelve examined antimicrobial drugs against clinical and fecal isolates of Clostridium perfringens type A. However, vancomycin and fosfomycin, which revealed suboptimal in vitro bactericidal activity, proved as efficacious as penicillin G and imipenem in an experimental mode of murine gas gangrene. Thus, conventional in vitro tests were not uniformly predictive for in vivo (murine) chemotherapeutic efficacy.
24 citations
TL;DR: Comparing the synthetic medium with the complex medium at either dilution rate, the volumetric rate of thienamycin production was higher in the system being fed complex medium, but the specific activity observed with complex medium was lower than that observed with synthetic medium.
Abstract: A novel 2-L bubble column was used to study the continuous, immobilized cell production of thienamycin. Cells of Streptomyces cattleya were immobilized by culturing them in an appropriate growth medium containing 60/80 mesh celite particles. The dilution rate used during the continuous growth phase was 0.2 h(-1). This growth phase was terminated upon the development of heavy cell films (100-500 mum thickness), and the medium was replaced with an appropriate thienamycin production medium. The system was then operated in a batch mode until thienamycin production began. At that time, continuous feeding of the production medium was initiated and the influence of medium composition and dilution rate on CO(2), NH(4), biomass, and thienamycin production investigated. With synthetic production medium, a doubling of the dilution rate from 0.05 to 0.10 h(-1) resulted in a doubling of the thienamycin volumetric productivity. Rates of CO(2) and NH(4) production increased by ca. factors of three and two, respectively. The rate of PO(4) utilization also doubled. When the dilution rate was decreased to 0.05 h(-1), the rates of CO(2) production and PO(4) utilization quickly decreased (i.e., within 3 h). The rates of NH(4) and thienamycin production also decreased but more slowly (i.e., ca. 100 h after the decrease in dilution rate). With complex production medium, the rates of CO(2) production and PO(4) utilization appeared to be a direct function of dilution rate at the dilution rates tested. Thienamycin production in this case was not a function of dilution rate. Comparing the synthetic medium with the complex medium at either dilution rate, the volumetric rate of thienamycin production was higher in the system being fed complex medium. However, the specific activity (units thienamycin/g cell/h) observed with complex medium was lower than that observed with synthetic medium. The higher volumetric productivity observed with complex medium was the result of a high cell loading. The above observations will be discussed in terms of control of thienamycin synthesis and film thickness effects.
22 citations
20 citations
TL;DR: The Biosynthesis of Thienamycin and Related Carbapenems: A Reviews in Biotechnology: Vol.
Abstract: (1986). The Biosynthesis of Thienamycin and Related Carbapenems. Critical Reviews in Biotechnology: Vol. 4, No. 1, pp. 111-131.
17 citations
TL;DR: In this article, the LD-carboxypeptidases of Escherichia coli K 12 and of a mutant strain 155 with reduced activities were studied with the aid of ether treated cells.
Abstract: The activities of the LD-carboxypeptidases of Escherichia coli K 12 and of a mutant strain 155 with reduced activities were studied with the aid of ether treated cells. Evidence was obtained that was consistent with the suggestion that in both strains two LD-carboxypeptidase activities are present. Activity I degrades the nucleotide activated precursor UDP-MurNAc-tetrapeptide and activity II splits off D-alanine residues from position 4 of the peptide subunits in the nascent murein. In the mutant strain activity I is reduced 10fold compared with strain K 12, whereas activity II is not affected. The two activities could be distinguished with regard to their sensitivity to D-amino acids and the beta-lactam antibiotic thienamycin.
TL;DR: Imipenem-cilastatin performed well in both comparative and noncomparative trials of clinical efficacy and safety and may be a cost-effective and less toxic single-agent alternative to "standard" combination therapy.
Abstract: The chemistry, antimicrobial spectrum, mechanism of action, pharmacology and pharmacokinetics, clinical use, adverse effects, dosage and administration, place in therapy, cost-effectiveness, and formulary considerations of imipenem-cilastatin sodium are reviewed. Imipenem is the first carbapenem antibiotic of the thienamycin class to be used clinically. Imipenem has the widest spectrum of antimicrobial activity of currently available beta-lactam agents and, in contrast to other beta-lactam antibiotics, lacks cross resistance with recently introduced extended-spectrum penicillins and third-generation cephalosporins. Against gram-positive and gram-negative aerobic and anaerobic organisms, imipenem demonstrates excellent activity. Pseudomonas maltophilia, some strains of Pseudomonas cepacia, and Streptococcus faecium are resistant. Strains of methicillin-resistant staphylococci should also be considered resistant to imipenem. For clinical use imipenem is coadministered in equal parts with cilastatin. Cilastatin is a renal dehydropeptidase inhibitor that inhibits the metabolism of imipenem by renal brush-border enzymes, thus increasing imipenem concentrations in urine. Imipenem-cilastatin is administered by the intravenous route only. The adverse reaction profile of imipenem-cilastatin is similar to t that of other beta-lactam antibiotics. Recommended dosage reductions appropriate for renal impairment should be guided by periodic assessments of renal function, with close adherence to recommended dosage schedules, particularly among patients who are predisposed to seizures or receiving anticonvulsant medication. Imipenem-cilastatin performed well in both comparative and noncomparative trials of clinical efficacy and safety. For infections with multiple organisms (e.g., pelvic, intra-abdominal, or soft-tissue infections), imipenem-cilastatin may be a cost-effective and less toxic single-agent alternative to "standard" combination (e.g., aminoglycoside-penicillin plus an antianaerobic agent) therapy. However, in patients with serious pseudomonal infections (e.g., pneumonia), isolates may rapidly acquire resistance to imipenem or be replaced by resistant strains of Ps. aeruginosa when imipenem is used alone. Therefore, when the recovery of Ps. aeruginosa is anticipated or documented, treatment with imipenem-cilastatin should include an aminoglycoside to reduce the likelihood of the emergency of resistant organisms during therapy.
TL;DR: In this paper, an α-silylethylidene-β-lactam was generated via CSI addition to a silylated allenyl sulphide and converted into a key intermediate for the synthesis of thienamycin.
Abstract: An α-silylethylidene-β-lactam is generated via chlorosulphonyl isocyanate (CSI) addition to a silylated allenyl sulphide and converted into a key intermediate for the synthesis of thienamycin.
TL;DR: Highly efficient internal chiral induction is achieved in the aldol-type reaction of tin(II) enolate generated from 3-amino-substituted butanoylthiazolidine-2-thione.
Abstract: Highly efficient internal chiral induction is achieved in the aldol-type reaction of tin(II) enolate generated from 3-amino-substituted butanoylthiazolidine-2-thione. This reaction is successfully applied to the formal total synthesis of (±)-thienamycin.
TL;DR: In this article, the synthesis of derivatives of the racemic carbapenem-3-carboxylic acid (3-CARBAC) has been studied and an analogue of the potent antibiotic thienamycin has been developed.
Abstract: Starting with the 4-oxoazetidine-2-carboxylic acids (3a) and (3b), methods for the synthesis of derivatives of the racemic carbapenem-3-carboxylic acid (2), an analogue of the potent antibiotic thienamycin have heen developed. The synthetic steps included chain elongations by the methods of Arndt-Eistert and Masamune, diazo group transfers, oxidative removals of N-protecting 2,4- dimethoxybenzyl and p-methoxyphenyl groups, cyclization involving a carbene insertion reaction, and conversion of the ketone moiety of the bicyclic compound (13b) into an enethiol moiety via enolphosphate activation. The target compound, the sodium salt (14c) did not possess any useful biological activity.
TL;DR: Treatment of Streptococcus faecium ATCC 9790 with sublytic concentrations of beta-lactam antibiotics revealed two different division blocks in the cell division cycle, suggesting that beta- lactamiotics have at least two sites of action in S. faecia.
Abstract: Treatment of Streptococcus faecium ATCC 9790 with sublytic concentrations of beta-lactam antibiotics revealed two different division blocks in the cell division cycle. One block, induced by N-formimidoyl thienamycin and methicillin, occurred before the completion of chromosome replication, whereas the other, induced by cefoxitin and cephalothin, took place later in the cycle. In addition, these antibiotics gave rise to distinct morphological forms; the antibiotics acting at the earlier block point produced mainly "dumbbells," whereas those affecting the later time formed "lemons." When used in combination N-formimidoyl thienamycin and cefoxitin exerted synergistic killing on this strain. These data suggest that beta-lactam antibiotics have at least two sites of action in S. faecium.
TL;DR: A partir de l'azetidinone du titre, on prepare des [oxo-4 azetidinyl-2]-4 butyne-2oates qui sont ensuite transformes en oxo- 4 azetidineacetylacetate-2; de la meme facon, synthese de t-butyldimethylsiloxy-1' ethyl-3 t-methylfunctional-3 synthetes.
Abstract: A partir de l'azetidinone du titre, on prepare des [oxo-4 azetidinyl-2]-4 butyne-2oates qui sont ensuite transformes en oxo-4 azetidineacetylacetate-2; de la meme facon, synthese de t-butyldimethylsiloxy-1' ethyl-3 t-butyldimethylsilyl-1 oxo-4 azetidineacetylacetate-2 de nitro-4 benzyle qui a deja ete transforme en (±)-thienamycine
TL;DR: Thienamycin derivatives (4) having a cyclic amidine moiety at the C-2 position and the antimicrobial activity of these compounds were determined and their structure-activity relationships are discussed.
Abstract: Thienamycin derivatives (4) having a cyclic amidine moiety at the C-2 position were prepared. The susceptibility to renal dehydropeptidase-1 and the antimicrobial activity of these compounds were determined. Their structure-activity relationships are also discussed.
TL;DR: In febrile granulocytopenic patients or other severely ill patients at risk of severe P. aeruginosa infections, thienamycin or another antipseudomonal beta-lactam should be combined with an aminoglycoside.
Abstract: The ureidopenicillins (piperacillin, mezlocillin, and azlocillin), aztreonam, and thienamycin are new broad-spectrum beta-lactams with more potent antibacterial activity than the older cephalosporins and penicillins. However, therapy of severe infections with the ureidopenicillins alone is limited by the potential for emergence of resistant organisms, while monotherapy with aztreonam does not provide adequate coverage for Gram-positive aerobic organisms and anaerobes. In combination therapy with the aminoglycosides, the ureidopenicillins may be preferred to carbenicillin or ticarcillin in the treatment of Pseudomonas aeruginosa infections and in institutions with a high prevalence of carbenicillin or ticarcillin-resistant organisms. Double beta-lactam therapy with piperacillin plus either latamoxef (moxalactam) or ceftazidime may be advantageous in patients for whom aminoglycoside toxicity is a concern. Thienamycin is the most promising of the new beta-lactams for single-agent therapy of severe infections but may also be associated with the emergence of resistant P. aeruginosa during monotherapy. In febrile granulocytopenic patients or other severely ill patients at risk of severe P. aeruginosa infections, thienamycin or another antipseudomonal beta-lactam should be combined with an aminoglycoside.
TL;DR: Synthese a partir d'acide (2S,3R)-bromo-2 hydroxy-3 butyrique (obtenu apartir de L-threonine) as discussed by the authors
Abstract: Synthese a partir d'acide (2S,3R)-bromo-2 hydroxy-3 butyrique (obtenu a partir de L-threonine)
TL;DR: The synthesis and in vitro antimicrobial activity of a new penem antibiotic, sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-ca rbo xylate (1), are reported.
Abstract: The synthesis and in vitro antimicrobial activity of a new penem antibiotic, sodium (5R, 6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-carboxylate (1), are reported. The MIC values of 1 are compared with those of some related 2-halcalkylthio penems prepared in this work, and also Sch 29482 and thienamycin.
Journal Article•
TL;DR: 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions and the in vitro antibacterial spectrum of 4-fluorothreonine is presented.
Abstract: An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate. THX was subsequently identified as one of the four possible stereoisomers of 4-fluorothreonine. Inorganic fluoride or any one of a number of organofluorine compounds can be used as precursors of 4-fluorothreonine. In addition, 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions. The in vitro antibacterial spectrum of 4-fluorothreonine is also presented.
TL;DR: In this paper, it was shown that NaBH4 reduction of the diazo ester (4d) gave mixtures of the diastereoisomers of the DIAZO esters (4e) and (20).
Abstract: The oxoazetidinecarboxylic acids (2a) and (2b) and the homologous acid (8b) were converted by treatment of their chlorides with ethyl diazoacetate into the diazo esters (4a, b), and (10b), respectively. Irradiation of the diazo ester (4b) afforded the diethyl and ethyl hydrogen malonates (17) and (18), respectively. Attempted thermal decarboxylation of the latter resulted in profound degradation to give a mixture of the isomeric compounds (19a, b). NaBH4 reduction at –78 °C of the diazo ester (4d) gave mixtures of the diastereoisomers of the diazo esters (4e) and (20). The (hydroxymethyl)-azetidinone (6b) was converted via the aldehyde (5b) and the nitroethyl derivative (22) into the acetals (23) and (25). Attempts to convert the nitrile (7a) into either the acid (8a) or the ester (9a) in acceptable yields, failed. The nitriles (7g) and (7e)[obtained in two steps from the nitrites (7c) and (7b), respectively] were converted by refluxing hydrochloric acid into Melillo's lactone (28)(the key intermediate of a practical synthesis of the carbapenem antibiotic thienamycin) and its N-unsubstituted analogue (30), respectively.
Patent•
22 Aug 1986
TL;DR: In this paper, a tartaric acid dimethyl ester (with asymmetric carbon atom, and including steric isomer) was shown by the formula I (Men is menthyl).
Abstract: NEW MATERIAL:A tartaric acid dimethyl ester (having asymmetric carbon atom, and including steric isomer) shown by the formula I (Men is menthyl). USE:A precursor for a glyoxylic acid methyl ester shown by the formula III (R and R' are bonded to show O) useful as a starting raw material for thienamycin compound or penem compound. PREPARATION:Tartaric acid is reacted with menthol in an inert solvent such as toluene, benzene, etc., in the presence of an acid such as p-toluenesulfonic acid, sulfuric acid, acidic ion exchange resin, etc., at 40-150 deg.C, to give a compound shown by the formula I.
TL;DR: In this article, L-Threonine was converted to a versatile azetidinone derivative stereospecifically in 3 steps, which was further transformed to (3S,4R)-3-[(R)-1-hydroxyethyl]-1-(4-methoxybenzyl)-4-[phenylthio)-carbonylmethyl]-2-azetinone (S-Phenyl thioester), a key intermediate for the synthesis of thienamycin and it's biologically active analogs.
Abstract: L-Threonine was converted to a versatile azetidinone derivative stereospecifically in 3 steps. This azetidinone was further transformed to (3S,4R)-3-[(R)-1-hydroxyethyl]-1-(4-methoxybenzyl)-4-[(phenylthio)-carbonylmethyl]-2-azetidinone (S-Phenyl thioester), a key intermediate for the synthesis of thienamycin and it’s biologically active analogs. Since the thiol part of this S-phenyl thioester can be exchanged easily with other complex or useful thiols under mild conditions, important S-thioester precursors for the production of carbapenem analogs were obtained in high yield.
TL;DR: Etude de reactions des acetyl-1 dimethyl-5,5 nitro-4″ benzyloxycarbonylamino-2' ethylthio- et -ethanesulfinyl-3 pyrroline-2carboxylates-2 de methyle
Abstract: Etude de reactions des acetyl-1 dimethyl-5,5 nitro-4″ benzyloxycarbonylamino-2' ethylthio- et -ethanesulfinyl-3 pyrroline-2carboxylates-2 de methyle