Deacetylcephalosporin C

Jeffery, J. D'a.; Abraham, E. P.; Newton, G. G. F.

doi:10.1042/bj0810591

Cited by 82 publications

(32 citation statements)

References 14 publications

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“…Incomplete urinary recoveries of cephalosporins such as cephalothin and cefotaxime have been ascribed to enzymatic (hepatic) cleavage of their acetylated side chains. In both instances, desacetyl metabolites with reduced antimicrobial activity and an intact beta-lactam are recovered in the urine of laboratory animals and in humans (6,7,9,20).…”

mentioning

confidence: 99%

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Kropp

Sundelof

Hajdu

et al. 1982

Antimicrob Agents Chemother

317

143

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Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787, and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys, and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I was found to catalyze the hydrolysis of the beta-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic Nacylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4-to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic infections in animals remain satisfactory.Thienamycin (THM) and the N-formimidoyl thienamycin derivative MK0787 are members of a new class of structurally novel beta-lactam antibiotics, the carbapenems. Both are known for their high orders of activity against a broad spectrum of bacteria (11,18,19). Their breadth of activity is in part attributable to resistance to attack by bacterial beta-lactamases (17).The low recovery of unaltered THM and MK0787 in the urine of laboratory animals suggested that these antibiotics are extensively metabolized. Incomplete urinary recoveries of cephalosporins such as cephalothin and cefotaxime have been ascribed to enzymatic (hepatic) cleavage of their acetylated side chains. In both instances, desacetyl metabolites with reduced antimicrobial activity and an intact beta-lactam are recovered in the urine of laboratory animals and in humans (6,7,9,20).Biochemical studies presented in this report show that low urinary recoveries of THM and MK0787 result from the hydrolysis of the betalactam ring by the renal dipeptidase, dehydropeptidase-I

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mentioning

confidence: 99%

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Kropp

Sundelof

Hajdu

et al. 1982

Antimicrob Agents Chemother

317

143

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“…These antibiotics inhibit cell growth by inhibiting the enzyme that cross-links peptide glycans required for cell wall formation (37). It has been shown that deacetylation of cephalosporin C leads to an 80% loss in activity against Staphylococcus aureus and Salmonella typhi (15). Thermoanaerobacterium sp.…”

Section: Discussionmentioning

confidence: 99%

Isolation, analysis, and expression of two genes from Thermoanaerobacterium sp. strain JW/SL YS485: a beta-xylosidase and a novel acetyl xylan esterase with cephalosporin C deacetylase activity

Lorenz

Wiegel

1997

J Bacteriol

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The genes encoding acetyl xylan esterase 1 (axe1) and a ␤-xylosidase (xylB) have been cloned and sequenced from Thermoanaerobacterium sp. strain JW/SL YS485. axe1 is located 22 nucleotides 3 of the xylB sequence. The identity of axe1 was confirmed by comparison of the deduced amino acid sequence to peptide sequence analysis data from purified acetyl xylan esterase 1. The xylB gene was identified by expression cloning and by sequence homology to known ␤-xylosidases. Plasmids which independently expressed either acetyl xylan esterase 1 (pAct1BK) or ␤-xylosidase (pXylo-1.1) were constructed in Escherichia coli. Plasmid pXylAct-1 contained both genes joined at a unique EcoRI site and expressed both activities. Substrate specificity, pH, and temperature optima were determined for partially purified recombinant acetyl xylan esterase 1 and for crude recombinant ␤-xylosidase. Similarity searches showed that the axe1 and xylB genes were homologs of the ORF-1 and xynB genes, respectively, isolated from Thermoanaerobacterium saccharolyticum. Although the deduced sequence of the axe1 product had no significant amino acid sequence similarity to any reported acetyl xylan esterase sequence, it did have strong similarity to cephalosporin C deacetylase from Bacillus subtilis. Recombinant acetyl xylan esterase 1 was found to have thermostable deacetylase activity towards a number of acetylated substrates, including cephalosporin C and 7-aminocephalosporanic acid.

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“…A culture of S. clavuligerus NRRL 3585, incubated for 48 hr in the fermentation medium, was centrifuged at 12,100 X g for 20 min at 4 C. A portion of the collected supernatant fluid was autoclaved for 30 min at 121 C. A second portion of the supernatant fluid was filtered through a 0.45-um membrane filter (Millipore Corp.). Samples (10 mnl) of the sterile filtered and autoclaved broths (pH 7.6 to 7.8) were dispensed into sterile tubes containing 10 mg of cephalosporin C-14C-9 (2.75 X 104 disintegrations per min per mg), and the tubes were incubated at 30 C. A sample of 1.5 ml was taken from each tube at 0, 3,6,12,20 mined. The sections of the chromatograms containing cephalosporin C-'4C-9 and deacetylcephalosporin C-G4C-9 were removed and minced, and the antibiotics were eluted with 3 ml of water.…”

Section: Methodsmentioning

confidence: 99%

Detection of a Cephalosporin C Acetyl Esterase in the Carbamate Cephalosporin Antibiotic-Producing Culture, Streptomyces clavuligerus

Brannon

Fukuda

Mabe

et al. 1972

Antimicrob Agents Chemother

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The possible role of a cephalosporin C acetyl esterase in the formation of the β-lactam antibiotic A16886A, 7-(5-amino-5-carboxyvaleramido)-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid, by Streptomyces clavuligerus was studied. Addition of dl -valine- 14 C-1 to a fermentation of Cephalosporium acremonium gave cephalosporin C- 14 C-9 (I). The formation of deacetylcephalosporin C- 14 C-9 from I occurred at a greater rate in broths of S. clavuligerus than in the broths of C. acremonium , or in the autoclaved broths of S. clavuligerus . Diisopropylfluorophosphate partially inhibited the deacetylation of I in S. clavuligerus broth. An intracellular cephalosporin C esterase in S. clavuligerus could not be demonstrated. Although A16886A has been chemically synthesized from deacetylcephalosporin C, this reaction could not be demonstrated with S. clavuligerus .

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Deacetylcephalosporin C

Cited by 82 publications

References 14 publications

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Isolation, analysis, and expression of two genes from Thermoanaerobacterium sp. strain JW/SL YS485: a beta-xylosidase and a novel acetyl xylan esterase with cephalosporin C deacetylase activity

Detection of a Cephalosporin C Acetyl Esterase in the Carbamate Cephalosporin Antibiotic-Producing Culture, Streptomyces clavuligerus

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