.beta.-Lactam antibiotics from Streptomyces

Nagarajan, Ramaswamy; Boeck, L. D.; Gorman, Marvin; Hamill, Robert L.; Higgens, C. E.; Hoehn, Marvin M.; Stark, W. Marshall; Whitney, J. G.

doi:10.1021/ja00738a035

Cited by 254 publications

(60 citation statements)

References 15 publications

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“…The mixture was stirred for 30 min, concentrated, and the residue was chromatographed on silica gel. Elution with qthylene chloride -methanol ( 1 0 : 1) gave 1 gen, and then placed under an oxygen atmosphere. The protected alcohol 25 (5 10 mg, 1.44 mmol) was added, and vigorous stirring was continued, under oxygen, for 12 h. The mixture was then centrifuged, the residue washed with water (2 X 2 mL), and the combined supernatant was evaporated under reduced pressure.…”

Section: -Acetoximino-2-phenylacetonitrilementioning

confidence: 99%

“…Streptomyces clavuligerus is a Gram positive, filamentous bacterium which produces a variety of P-lactam compounds including penicillin N, cephamycin C, and clavulanic acid (1,2). The biosynthetic versatility of this organism, in terms of the synthesis of p-lactam compounds, has prompted an investigation of the enzymatic steps involved in the natural production of these antibiotics (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Penicillin formation by cell-free extracts of Streptomycesclavuligerus. Behaviour of aminoadipyl-modified analogs of the natural peptide precursor δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV)

Jensen¹,

Westlake²,

Bowers³

et al. 1984

Can. J. Chem.

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. Can. J. Chem. 62, 27 12 (1984). Six analogs of ACV, the biosynthetic precursor of the penicillin nucleus, have been synthesized, in which the 6-(L-a-aminoadipyl) moiety has been replaced by : P-(L-aspartyl), y-(L-glutamyl), 6-(D-a-aminoadipyl), adipyl, glycyl-6-(L-a-aminoadipyl), and N-acetyl-6-(L-a-aminoadipyl). The penicillins having the adipyl, glycyl-6-(L-a-aminoadipyl), and N-acetyl-6-(L-a-aminoadipyl) side chains have also been synthesized. Several improvements have been made in earlier routes to ACV and related peptides, including a simplified preparation of a dipeptide precursor, and a new synthesis of a-aminoadipic acid from lysine. A new reagent, 2-acetoximino-2-phenylacetonitrile, has been synthesized, which allows ready N-acetylation of amino hydroxyacids in aqueous acetone at room temperature. The peptide analogs have been examined as substrates of the enzyme isopenicillin N synthetase, which converts ACV to isopenicillin N in the presence of oxygen, ferrous ions, and ascorbate. The enzyme has been isolated from the prokaryotic organism Streptomyces clavuligerus, and has been employed either as a crude salt precipitate or in semi-purified form, freed from other enzymes of the penicillin-cephalosporin pathway. With the crude enzyme preparation, three of the analogs are active substrates, viz., adipyl, glycyl-6-(L-a-aminoadipyl), and N-acetyl-6-(L-a-aminoadipyl), but the latter two are converted, only via ACV, to isopenicillin N, the normal cyclization product. That the crude enzyme preparation contains a protease that deacylates N-substituted ACV analogs to ACV is confinned, inter alia, by the behaviour of the purified enzyme; of the various analogs, only the adipyl compound is an active substrate, but the conversion of this analog to carboxybutylpenicillin proceeds with only 1 -2%.efficiency, compared to the natural substrate. On a synthCtisC six analogues de I'ACV, le precurseur biosynthttique du noyau de la pknicilline, dans lesquel on a remplacC I'unitC 6-(L-a-aminoadipyl) par les unitts suivantes: P-(L-aspartyl), y-(L-glutamyl), 6-(D-a-aminoadipyl), adipyl, glycyl-6-(L-a-aminoadipyl) et N-acCtyl-6-(L-a-aminoadipyl). On a Cgalement synthCtisC des ptnicillines ayant des groupes adipyl, glycyl-6-(L-a-aminoadipyl) et N-acCtyl-6-(L-a-aminoadipyl) comme chaines lattrales. On a apportt plusieurs ameliorations aux voies d'accts a 1'ACV et aux peptides apparent& que nous avions dtcrites anttrieurement; ces amiliorations comprennent entre autre une prkparation simplifiCe d'un dipeptide prkcurseur ainsi qu'une nouvelle synthtse de I'acide a-aminoadipique a partir de la lysine. On a synthCtisC un nouveau reactif, I'acCtoxymino-2 phenyl-2 acitonitrile, qui permet d'effectuer facilement une N-acCtylation des hydroxy-acides amints en opirant dans l'acttone aqueuse et a la temperature ambiante. On a CtudiC le comportement des analogues peptidiques comme substrats de l'enzyme isopCnicilline N-synthktase qui transforme I'ACV en iso@nicilline N en presence d'oxygkne, d'ions ferreux et d'ions ascorbate. On a isol...

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Section: -Acetoximino-2-phenylacetonitrilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Penicillin formation by cell-free extracts of Streptomycesclavuligerus. Behaviour of aminoadipyl-modified analogs of the natural peptide precursor δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV)

Jensen¹,

Westlake²,

Bowers³

et al. 1984

Can. J. Chem.

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“…Another organism, Streptomyces lipmanii (Waksman and Curtis) Waksman and Henrici, strain NRRL 3584, was isolated from a different soil sample from the same locality and likewise was found to produce a new cephalosporin antibiotic, 7-(5-amino-5-carboxyvaleramid 0)-7 -methoxycephalosporanic acid (6). Both organisms also produce penicillin N, an antibiotic previously reported from a streptomycete by Miller et al (Bacteriol.…”

mentioning

confidence: 82%

“…o x y m e thyl-7-methoxy-3-cephem-4-carboxylic acid (6). Another organism, Streptomyces lipmanii (Waksman and Curtis) Waksman and Henrici, strain NRRL 3584, was isolated from a different soil sample from the same locality and likewise was found to produce a new cephalosporin antibiotic, 7-(5-amino-5-carboxyvaleramid 0)-7 -methoxycephalosporanic acid (6).…”

mentioning

confidence: 99%

Streptomyces clavuligerus sp. nov., a -Lactam Antibiotic Producer

Higgens

Kastner

1971

International Journal of Systematic Bacteriology

109

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A new species of Streptomyces which produces two new cephalosporin antibiotics is named and described. Sporophores are produced on an extensive aerial mycelium and consist of networks of short, sympodially branched hyphae. One to four spores are borne usually on short, club-shaped side branches. Sporophores eventually segment to form chains of spores. The spores are oblong to slightly cylindrical, smooth-walled, and gray to grayish green en masse. The species name proposed, Streptomyces clavuligerus, refers to the production of club-like side branches.A previously undescribed streptomycete isolated from a South American soil sample by a selective isolation procedure was found to produce two new cephalosporin antibiotics, Henrici, strain NRRL 3584, was isolated from a different soil sample from the same locality and likewise was found to produce a new cephalosporin antibiotic, 7-(5-amino-5-carboxyvaleramid 0)-7 -methoxycephalosporanic acid (6). Both organisms also produce penicillin N, an antibiotic previously reported from a streptomycete by Miller et al. (Bacteriol. Proc., p. 32, 1962). The former organism is believed to be a new species in the genus Streptomyces Waksman and Henrici, and in this report the new species is named, described, and assigned a type strain. MATERIALS AND METHODSIsolation of bacterial strain. The organism was selected from a series of soil isolations that were plated at dilutions of 1:103 to 1:105 on a modified Pridham and Gottlieb basal medium (7), supplemented with 0.5% glucose. Unsterilized nystatin (E. R. Squibb and Sons, New York, N.Y.) at 30 mg/liter was added to the melted agar before dilution plates were poured. Inoculated plates were incubated at 30 C for 10 days.Method. The methods and media recommended by the International Streptomyces Project (ISP; 10) were used primarily, along with several supplementary tests.Stock slant cultures were maintained on ISP no. 2 (yeast-malt) agar. These slants, as well as subsequent cultures used in this study, were incubated at 30C. Inocula were prepared by transferring a loopful of spores from an agar slant into a 250-ml flask containing 70 ml of tryptone-yeast extract broth (7). Flasks were incubated on a rotary shaker [2-inch (5 cm) stroke, 250 rev/min] for 72 hr. Broth cultures were macerated for 30 sec in an homogenizer, centrifuged, and then suspended in 0.85% sterile saline. Inocula for carbon-utilization tests were washed twice and suspended in saline.Microscopic observations were made on cultures that were grown from 4 to 21 days on ISP no. 4 (inorganic saltsstarch), Bennett's, and ISP no. 5 (glycerol-asparagine) media. Sporophore morphology was observed on undisturbed plate cultures, and slide mounts were stained with 0.1% Acid Fuchsin in lactic acid-glycerol (1 :

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“…Impure leading and tailing fractions were combined and purified by preparative thin-layer chromatography [silica gel, E. Merck 60F, CH2Cl2 -EtOAc (2: 1)]. The combined purified product was solidified by precipitation from an ether -pentane mixture (total yield: 1.82g, 50%); 1H NMR (CDCL,) 5 713-Acetylaniino-7-methoxydesacetoxycephalosporanic Acid (8) A solution of cephem ester 7 (1.67 g, 3.69 mmole) in a mixture of anisole (2 ml) and CH2Cl2 (20 ml), cooled in an ice bath, was treated with trifluoroacetic acid (4 ml) for 4.5 hours. Solvent was removed in vacuo giving a residual oil which, after washing with pentane, was solidified and triturated with an ether-pentane mixture yielding acid 8 as a colorless powder (1.…”

Section: Sulfeniminementioning

confidence: 99%

SQ 26,180, a novel monobactam. II. Isolation, structure determination and synthesis.

Parker¹,

Koster²,

Cimarusti

et al. 1982

J. Antibiot.

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A novel monocyclic i-lactam antibiotic SQ 26,180 has been isolated from bacteria and the structure, (R)-3-acetylamino-3-methoxy-2-oxo-l-azetidinesulfonic acid was deduced from its spectroscopic properties. Structural confirmation and assignment of absolute configuration were made by synthesis from 6-aminopenicillanic acid.Beta-lactam antibiotics comprise one of the major chemotherapeutic means for the control of bacterial infections. This group of antibiotics has been the subject of intensive research in recent years, leading to the discovery of several new classes of naturally occurring ;S-lactams, namely the cephamycins, nocardicins, clavulanic acids and a burgeoning family of carbapenems. We now wish to report the isolation and characterization of a strongly acidic monocyclic ~-lactam antibiotic, SQ 26,180, a member of a new class of ji-lactam antibiotics, discovered independently by workers at both Takeda" and Squibb2) for which we have suggested the generic term "monobactam".SQ 26,180, produced by fermentations of Chromobacterium violaceum SC 11,378, was shown to have structure 1, (R)-3-acetylamino-3-methoxy-2-oxo-l-azetidinesulfonic acid. Isolation of SQ 26,180 was monitored using sensitive strains of Bacillus licheniformis and Pseudomonas aeruginosa. The characterization of the producing organism and the fermentation are described in the accompanying paper.3) SQ 26,180 was isolated from fermentation broths as outlined in Fig. 1.The antibiotic was extracted into dichloromethane containing a tetraalkylammonium salt, cetyldimethylbenzylammonium chloride being effective for this purpose. Back extraction of SQ 26,180

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.beta.-Lactam antibiotics from Streptomyces

Cited by 254 publications

References 15 publications

Penicillin formation by cell-free extracts of Streptomycesclavuligerus. Behaviour of aminoadipyl-modified analogs of the natural peptide precursor δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV)

Penicillin formation by cell-free extracts of Streptomycesclavuligerus. Behaviour of aminoadipyl-modified analogs of the natural peptide precursor δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV)

Streptomyces clavuligerus sp. nov., a -Lactam Antibiotic Producer

SQ 26,180, a novel monobactam. II. Isolation, structure determination and synthesis.

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