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PubMed1969

Analysis of the chloramphenicol-sensitive and chloramphenicol-resistant steps in the initiation of DNA synthesis in E. coli B-r.

Two processes that are required for the initiation of a new round of bacterial DNA synthesis and which are blocked by low and high concentrations of chloramphenicol, respectively, have been examined in order to determine the cell age at which each of these processes occurs as a function of growth rate. The timing of these steps in the life cycle was determined by observing changes in the variation with cell age of the rate of DNA synthesis during growth in medium containing chloramphenicol of the desired concentration. For cell-doubling times ranging from 27 to 49 minutes, it was found that the step which is resistant to low concentrations of chloramphenicol occurs at the cell age at which a new round of DNA synthesis is initiated. The chloramphenicol-sensitive step was found to occur about 21 minutes before the start of rounds, independent of growth rate for doubling times between 27 and 49 minutes. For doubling of times 41 minutes or less, the chloramphenicol-sensitive processes occurred within five minutes after cell division.

Chloramphenicol↗
PubMed1986

Pharmacokinetic, residue and irritation aspects of chloramphenicol sodium succinate and a chloramphenicol base formulation following intramuscular administration to ruminants.

The disposition of chloramphenicol (CAP) and of its glucuronide metabolite in plasma and milk was studied following a single intramuscular injection of a chloramphenicol base formulation (Amicol Forte; product A) and of chloramphenicol sodium succinate (product B) to dairy cows. The dose applied of both formulations was equivalent to 50 mg CAP base/kg body weight. The HPLC determined CAP concentrations were microbiologically active. Product A revealed 30% higher plasma CAP peak concentrations (13.0 vs 9.0 micrograms/ml) and 36% larger areas under the plasma concentration-time curves than product B, whereas their absorption and elimination half-lives were of the same order of magnitude. In the onset phase (during 4 h p.i.) unhydrolysed CAP sodium succinate could be detected in plasma and the glucuronide fraction was 26% of the parent drug. After 25 h p.i. the glucuronide fraction equalled that of the parent drug. The maximum CAP concentration in milk was for product B equal to, and for product A 80% of, the CAP plasma concentration. In milk no chloramphenicol glucuronide metabolites could be detected. HPLC methods for detecting ultra-trace CAP concentrations in edible tissues were developed by the employment of extraction with or without a clean-up procedure. Seven days after i.m. administration of product A and B to calves, the CAP residue concentrations in the kidney, liver, and muscle were less than 2 nanogram/g tissue. Traces of CAP residues could be still found at the injection site and in the urine. Chloramphenicol sodium succinate (product B) caused extensive tissue irritation at the injection site, while in the case of product A the irritation was limited.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Differential in-vitro toxicity of chloramphenicol, nitroso-chloramphenicol, and thiamphenicol.

The comparative effects of chloramphenicol, its nitroso derivative, and thiamphenicol on a number of metabolic parameters in vitro, including DNA and mitochondrial protein synthesis, and the effects of these agents on isolated double-stranded DNA are described. Evidence is presented in support of the hypothesis that the p-nitro group of chloramphenicol is the structural feature underlying aplastic anemia caused by this drug. The capacity of small concentrations of nitroso-chloramphenicol and large concentrations of chloramphenicol to produce breaks in double-stranded DNA suggests that, in the predisposed host, either chloramphenicol or its nitroso derivative may cause DNA damage and mutation, ultimately leading to aplastic anemia and/or leukemia.

Cell Cycle↗
PubMed1975

Chloramphenicol binding site with analogues of chloramphenicol and puromycin.

The effect of a series of puromycin analogues and aminoacyl chloramphenicol derivatives on poly(U,C)-directed polyphenylalanine synthesis in an Escherichia coli cell-free system was examined. A comparison between the structures and activities of the puromycin and chloramphenicol analogues was made to examine the proposal that ribosomal binding sites for both antibiotics overlap. Our results suggest that the dichloroacetamido group in the chloramphenicol molecule does not correspond to the role of the aminoacyl moieties of either puromycin or aminoacyl transfer ribonucleic acid. These results comparing the structures and activities of puromycin and chloramphenicol analogues also seem inconsistent with a common binding site for the p-substituted phenyl moieties of the two antibiotics. Previous data have indicated that both sites are mutually affected by the prior binding of either antibiotic. Although it is possible that chloramphenicol and puromycin may have overlapping bindings sites, no common structural features between the two antibiotics are supported by our data.

Binding Sites↗
PubMed1968

Characterization of chloramphenicol acetyltransferase from chloramphenicol-resistant Staphylococcus aureus.

Chloramphenicol-resistant strains of Staphylococcus aureus contain an inducible enzyme which inactivates chloramphenicol by acetylation in the presence of acetyl coenzyme A. The products of acetylation are chromatographically indistinguishable from those obtained with chloramphenicol-resistant Escherichia coli harboring an R factor. The kinetics of induction of chloramphenicol acetyltransferase are complicated by the inducer's effect on protein biosynthesis and its fate as chloramphenicol 3-acetate, which is not an inducer of the enzyme. The E. coli and S. aureus enzymes have been compared, with the conclusion that they are identical with respect to molecular weight (approximately 78,000) and pH optimum (7.8), but differ with respect to heat stability, substrate affinity, electrophoretic mobility, and immunological reactivity. Antiserum prepared against enzyme from E. coli contains precipitating antibody, which inactivates the E. coli enzyme, but neither precipitates nor neutralizes the activity of S. aureus enzyme.

Acyltransferases↗
PubMed2007

Efflux-mediated resistance to florfenicol and/or chloramphenicol in Bordetella bronchiseptica: identification of a novel chloramphenicol exporter.

OBJECTIVES: Twenty florfenicol- and/or chloramphenicol-resistant Bordetella bronchiseptica isolates of porcine and feline origin were investigated for the presence of floR and cml genes and their location on plasmids. METHODS: The B. bronchiseptica isolates were investigated for their susceptibility to antimicrobial agents by broth micro- or macrodilution and for their plasmid content. Hybridization experiments and PCR assays were conducted to identify resistance genes. Transformation and conjugation studies were performed to show their transferability. Representatives of both types of genes including their flanking regions were sequenced. Moreover, inhibitor studies with the efflux pump inhibitor Phe-Arg-beta-naphthylamide (PAbetaN) were performed. RESULTS: The gene floR was found in the chromosomal DNA of 9 of the 18 florfenicol/chloramphenicol-resistant isolates. Sequence analysis revealed that the deduced FloR protein sequence differed by a single amino acid exchange from FloR of Vibrio cholerae. A chloramphenicol-resistant, but florfenicol-susceptible isolate carried a novel plasmid-borne cml gene, designated cmlB1. The CmlB1 protein revealed only 73.8-76.5% identity to known CmlA proteins. The gene cmlB1 was not part of a gene cassette. The results of inhibitor studies with PAbetaN suggested that a so-far unidentified efflux system might play a role in phenicol resistance of the remaining florfenicol- and/or chloramphenicol-resistant isolates. CONCLUSIONS: This is to the best of our knowledge the first report of a floR gene in B. bronchiseptica isolates. The identification of the first member of a new subclass of cml genes, cmlB1 from B. bronchiseptica, extends our knowledge on specific chloramphenicol exporters.

Amino Acid Sequence↗
PubMedDate not supplied

The identification and characterisation of chloramphenicol-aldehyde, a new human metabolite of chloramphenicol.

The toxic aldehyde derivative of chloramphenicol has previously been reported as a metabolic product only in the rat. Chloramphenicol-aldehyde has been synthesised and characterised and shown to exist in at least two forms, possibly due to rearrangement within the molecule. The authenticated compound has been used to identify chloramphenicol-aldehyde as a metabolic product excreted in the urine of children treated with chloramphenicol.

Child↗
PubMed1977

Chloramphenicol acetylransferase-independent chloramphenicol resistance in Streptomyces coelicolor A3(2).

Streptomyces coelicolor A3(2) and S. lividans 66, which lack chloramphenicol acetyltraferase, gave rise to vhloramphenicol-sensitive (CmlS) variants spontaneously at frequencies of 0-5 to 2%. The fertility type of S. coelicolor in respect of the SCPI plasmid (SCPI+, SCPI- or NF) had no effect on chloramphenicol sensitivity or on the frequency at which CmlS variants arose. CmlS isolates spontaneously reverted to CmlR at frequencies one to three orders of magnitude lower than the frequency with which CmlS strains arose from CmlR. CmlR revertants obtained spontaneously from CmlS clones again produced CmlS isolates at the normal frequency of several per cent. Therefore, CmlS and CmlR are reversible phenotypes. In crosses between marked CmlR and CmlS S. coelicolor strains, transfer of chloramphenicol resistance into the sensitive strain apparently occurred independently of chromosomal recombination. Mapping experiments excluded the possibility that segregation of a chromosomal locus determines CmlR versus CmlS phenotype. In crosses between SCPI- strains, fertility was not significantly different in CmlR x CmlS, CmlR x CmlR and CmlS x CmlS combinations. Covalently closed circular DNA from CmlS and CmlR strains of S. coelicolor was indistinguishable in molecular weight and restriction endonuclease cleavage pattern. It is suggested that chloramphenicol resistance in S. coelicolor A3(2) is affected by some kind of transposable genetic element that may be capable of extra-chromosomal existence.

Acetyltransferases↗
PubMed1962

Mode of action of chloramphenicol. VII. Growth and multiplication of Escherichia coli in the presence of chloramphenicol.

Allison, James L. (Walter Reed Army Institute of Research, Washington, D. C.), Richard E. Hartman, Roberta S. Hartman, Alan D. Wolfe, Jennie Ciak, and Fred E. Hahn. Mode of action of chloramphenicol. VII. Growth and multiplication of Escherichia coli in the presence of chloramphenicol. J. Bacteriol. 83:609-615. 1962.-Significant increases in both total and viable numbers of bacteria in cultures of Escherichia coli B/r were shown to occur in the presence of "bacteriostatic concentrations" (50 mug/ml) of chloramphenicol. Bacterial viability began to decline between one and two generation times after the addition of the antibiotic. It is inferred that unbalanced growth and cellular division occurring in the absence of protein synthesis give rise to physiologically inhomogeneous bacterial populations. Analytical studies on such populations, therefore, do not necessarily determine events that are typical for all individual bacteria in the culture. These considerations emphasize further the need for elucidating the primary action of chloramphenicol in isolated, cell-free systems that are free of physiological complications.

Anti-Bacterial Agents↗
PubMed1990

Chloramphenicol resistance in Streptomyces: cloning and characterization of a chloramphenicol hydrolase gene from Streptomyces venezuelae.

A 6.5 kb DNA fragment containing a chloramphenicol-resistance gene of Streptomyces venezuelae ISP5230 was cloned in Streptomyces lividans M252 using the high-copy-number plasmid vector pIJ702. The gene was located within a 2.4 kb KpnI-SstI fragment of the cloned DNA and encoded an enzyme (chloramphenicol hydrolase) that catalysed removal of the dichloroacetyl moiety from the antibiotic. The deacylated product, p-nitrophenylserinol, was metabolized to p-nitrobenzyl alcohol and other compounds by enzymes present in S. lividans M252. Examination of the genomic DNA from several sources using the cloned 6.5 kb SstI fragment from S. venezuelae ISP5230 as a probe showed a hybridizing region in the DNA from S. venezuelae 13s but none in the DNA from another chloramphenicol producer, Streptomyces phaeochromogenes NRRLB 3559. The resistance phenotype was not expressed when the 6.5 kb SstI fragment or a subfragment was subcloned behind the lac-promoter of plasmid pTZ18R in Escherichia coli.

Amidohydrolases↗
PubMed2001

Chloramphenicol-sensitive Escherichia coli strain expressing the chloramphenicol acetyltransferase (cat) gene.

An Escherichia coli strain (strain CM2555) bearing the chloramphenicol acetyltransferase (cat) gene was found to be sensitive to chloramphenicol. We demonstrate that the cat gene is efficiently expressed in strain CM2555. Our results suggest that decreased levels of acetyl coenzyme A in cat-expressing CM2555 cells in the presence of chloramphenicol may cause the bacterium to be sensitive to this antibiotic.

Acetyl Coenzyme A↗
PubMed1987

In vitro chloramphenicol susceptibility testing of Haemophilus influenzae: disk diffusion procedures and assays for chloramphenicol acetyltransferase.

The activity of chloramphenicol against 100 different strains of Haemophilus influenzae was assessed by a macrotube broth dilution technique and by a standardized disk diffusion method using both enriched chocolate agar (CHOC) and Mueller-Hinton agar containing 1.0% hemoglobin and 1.0% IsoVitaleX (BBL Microbiology Systems, Cockeysville, Md.) supplement (CHOC-MHA). Filter disks containing 30 micrograms of chloramphenicol were used with the disk diffusion procedure. The following zone diameter interpretive criteria were defined: CHOC-MHA, less than or equal to 25 mm = resistant [corrected] and greater than or equal to 26 mm = susceptible [corrected]; CHOC, less than or equal to 28 mm = resistant [corrected] and greater than or equal to 29 mm = susceptible [corrected]. all of the H. influenzae strains examined were also characterized by using two rapid assays for chloramphenicol acetyltransferase (CAT) activity: a 1-h tube method (t-CAT) and a 30-min procedure which used commercially available reagent-impregnated disks (d-CAT). The t-CAT procedure was found to be significantly more accurate than the d-CAT procedure as a means for demonstrating production of CAT.

Acetyltransferases↗
PubMed1999

Cubic crystals of chloramphenicol phosphotransferase from Streptomyces venezuelae in complex with chloramphenicol.

Chloramphenicol 3-O-phosphotransferase (CPT) from Streptomyces venezuelae ISP5230, a novel chloramphenicol-inactivating kinase, has been overexpressed and purified using Escherichia coli as the heterologous host. Crystals of CPT in complex with its substrate chloramphenicol (Cm) were obtained which were suitable for X-ray diffraction. The crystals belong to the cubic space group I4132 with unit-cell dimension a = 200.0 A. The initial CPT crystals diffracted to 3.5 A and the diffraction was improved significantly upon adding acetonitrile and Cm to the crystallization drop. The CPT-Cm crystals diffract to at least 2.8 A resolution.

Bacterial Proteins↗
PubMed1973

Mechanism of chloramphenicol resistance in staphylococci: characterization and hybridization of variants of chloramphenicol acetyltransferase.

Fifty clinical isolates of chloramphenicol-resistant staphylococci from diverse sources were screened for the presence of chloramphenicol acetyltransferase (CAT) and were found to contain the inducible chloramphenicol-inactivating enzyme in each case. Polyacrylamide disc gel electrophoresis revealed four distinct types of CAT of which three were purified to a state of homogeneity. Each purified CAT preparation was shown to exist as a tetrameric protein with a native molecular weight of 80,000 and an identical subunit size of 20,000. All four staphylococcal types of CAT exhibited identical catalytic and immunological properties, but they possessed variable sensitivity to heat denaturation and to inhibition by mercuric ion. Each of the three purified variants of staphylococcal CAT was capable of undergoing reversible denaturation in 6 m guanidine hydrochloride. In vitro hybridization was successful between pairs of each of the three purified staphylococcal enzymes. Only one heteromeric (hybrid) species was observed in addition to the parental types rather than the three predicted from the known quaternary structure of staphylococcal CAT.

Acetyltransferases↗
PubMed1977

Effects of concurrent drug therapy and of feeding on plasma chloramphenicol levels after oral administration of chloramphenicol in dogs.

On separate occasions, five fasted adult greyhounds were dosed orally with 50 mg chloramphenicol/kg, both alone and in conjunction with other drugs. The same five dogs were later given 50 mg chloramphenicol/kg when fed ad lib. Chloramphenicol levels in plasma were determined at intervals after dosing. The intial plasma chloramphenicol levels were higher when the drug was administered concurrently with calcium lactate tablets (50 mg/kg) or a proprietary enteric mixture containing kaolin, pectin, aluminium hydroxide and belladonna extract. Lower plasma levels resulted when the antibiotic was given with dry extract of belladonna (20 mg/dog) or intravenous chlorpromazine (2 mg/kg). There was no significant effect with coated ferrous gluconate tablets (30 mg/kg). Feeding ad lib increased the initial chloramphenicol levels, but produced lower levels subsequently.

Administration, Oral↗
PubMed1994

Emerging chloramphenicol resistance in Staphylococcus lentus from mink following chloramphenicol treatment: characterisation of the resistance genes.

A total of 26 staphylococcal strains isolated from mink with urinary tract infections as well as from the environment of the mink were examined for antibiotic resistance and prevalence of plasmids mediating resistance to the antibiotics applied for prophylactic or therapeutic purposes. Chloramphenicol resistance (Cmr) which occurred in fourteen of the eighteen Staphylococcus lentus strains, but in none of the Staphylococcus intermedius and Staphylococcus xylosus strains, was shown to be mediated by small plasmids of 3.6 to 4.6 kb. On the basis of restriction endonuclease mapping and hybridization experiments, four different types of Cmr plasmids, designated pSCS14-17, could be distinguished. All these plasmids conferred Cmr by encoding the Cm-inactivating enzyme chloramphenicol acetyltransferase (CAT). In all four types of Cmr plasmids from S. lentus, the expression of the cat gene was inducible with Cm, as demonstrated by enzymatic assay and polyacrylamide gel electrophoresis.

Animals↗
PubMed2001

Structural basis for chloramphenicol tolerance in Streptomyces venezuelae by chloramphenicol phosphotransferase activity.

Streptomyces venezuelae synthesizes chloramphenicol (Cm), an inhibitor of ribosomal peptidyl transferase activity, thereby inhibiting bacterial growth. The producer escapes autoinhibition by its own secondary metabolite through phosphorylation of Cm by chloramphenicol phosphotransferase (CPT). In addition to active site binding, CPT binds its product 3-phosphoryl-Cm, in an alternate product binding site. To address the mechanisms of Cm tolerance of the producer, the crystal structures of CPT were determined in complex with either the nonchlorinated Cm (2-N-Ac-Cm) at 3.1 A resolution or the antibiotic's immediate precursor, the p-amino analog p-NH(2)-Cm, at 2.9 A resolution. Surprisingly, p-NH(2)-Cm binds CPT in a novel fashion. Additionally, neither 2-N-Ac-Cm nor p-NH(2)-Cm binds to the secondary product binding site.

Bacterial Proteins↗