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Biomedical subjects

R B Sykes

Publications and source records attributed to R B Sykes.

At least 37 records · Page 2Linked to original sources
PubMed1984

Cepacin A and cepacin B, two new antibiotics produced by Pseudomonas cepacia.

Two new acetylenic antibiotics, cepacins A and B, have been isolated from the fermentation broth of Pseudomonas cepacia SC 11,783 and assigned structures 1 and 2. Cepacin A has good activity against staphylococci (MIC 0.2 micrograms/ml) but weak activity against streptococci (MIC 50 micrograms/ml) and the majority of Gram-negative organisms (MIC values 6.3 approximately greater than 50 micrograms/ml). Cepacin B has excellent activity against staphylococci (MIC less than 0.05 micrograms/ml) and some Gram-negative organisms (MIC values 0.1 approximately greater than 50 micrograms/ml).

Anti-Bacterial Agents↗
PubMed1983

Binding of monobactams to penicillin-binding proteins of Escherichia coli and Staphylococcus aureus: relation to antibacterial activity.

A series of novel monocyclic beta-lactam antibiotics having side chains related to penicillin, piperacillin, azlocillin, and cefotaxime were examined with respect to binding to essential penicillin-binding proteins (PBPs) in Escherichia coli and Staphylococcus aureus. In the penicillin series, there was poor binding to all essential PBPs of E. coli (greater than 100 micrograms/ml) but good binding to PBPs 1, 2, and 3 of S. aureus (approximately 1 microgram/ml). In the piperacillin and azlocillin series, there was good binding to PBP 3 of E. coli (0.1 microgram/ml) and PBPs 1, 2, and 3 of S. aureus (approximately 1 microgram/ml). In the cefotaxime series, there was generally good binding to PBP 3 of E. coli (0.1 micrograms/ml) but poor binding to PBPs 1, 2, and 3 of S. aureus (greater than or equal to 100 micrograms/ml). With a few exceptions in the cefotaxime series, antibacterial activity paralleled essential PBP binding. Binding studies with radioactively labeled compounds revealed no additional essential monobactam-binding proteins in the two organisms. The studies suggest that monobactams are intrinsically active against both gram-positive and gram-negative bacteria; the activity spectrum of a given monobactam is determined by the binding to essential PBPs, which in turn is determined by the nature of the substituents on the beta-lactam nucleus.

Aminoacyltransferases↗
PubMed1983

High-pressure liquid chromatographic analysis of aztreonam in sera and urine.

Aztreonam (SQ 26,776) is a new synthetic monocyclic beta-lactam antibiotic which is specifically active against aerobic gram-negative bacteria. High-pressure liquid chromatographic (HPLC) systems were developed for the quantitative analysis of aztreonam in human, monkey, rat, mouse, and rabbit sera and urine. The HPLC conditions employed for these analyses were a muBondapak C18 column, a mobile phase made up of 0.005 M tetrabutylammonium hydrogen sulfate at pH 3.0 and acetonitrile or methanol, UV detection at 293 nm, and a flow rate of 2.0 ml/min. For human sera and urine, the mobile phase was 80% 0.005 M tetrabutylammonium hydrogen sulfate-0.005M (NH4)2SO4 and 20% acetonitrile (vol/vol). For the range of sera and urine, HPLC analyses were shown to have excellent detector linearity of aztreonam over a concentration range of 1.0 mg/ml to 0.5 microgram/ml. Correlation coefficients for plots of aztreonam peak area versus its concentration were greater than or equal to 0.990. The detection limit of aztreonam was 1.0 micrograms/ml in sera and 5.0 micrograms/ml in urine. HPLC and microbiological assays of aztreonam in human sera and urine were in good agreement.

Animals↗
PubMed1983

Two new monobactam antibiotics produced by a Flexibacter sp. I. Taxonomy, fermentation, isolation and biological properties.

Two new beta-lactam antibiotics, namely SQ 28,502 and SQ 28,503, have been isolated from fermentations of a Flexibacter sp. They are demethoxy monobactams with oligopeptide side chains and have molecular weights of 1,462 and 1,446, respectively. These beta-lactams show a high degree of stability to a variety of beta-lactamases and act as potent irreversible inactivators of P99 beta-lactamase from Enterobacter cloacae. They exhibit weak antibacterial activity.

Anti-Bacterial Agents↗
PubMed1983

Penicillin-binding proteins in Bacteroides fragilis.

The penicillin binding proteins (PBSs) of Bacteroides fragilis, a clinically important Gram-negative rod, were studied. Four PBPs were detected by polyacrylamide gel electrophoresis/fluorography, PBP 4 (molecular weight, 35,000) being a minor PBP. The PBP pattern was thus different from that of the Enterobacteria and Pseudomonads. Antibacterial activity of beta-lactam antibiotics was associated with binding to PBP 1 (molecular weight, 100,000), 2 (molecular weight, 86,000) and 3 (molecular weight, 68,000). Binding to PBP 2 was associated with filamentation while binding to PBP 1 resulted in cell lysis.

Bacterial Proteins↗
PubMed1982

Activity of sulfa drugs and dihydrofolate reductase inhibitors against Candida albicans.

Growth of Candida albicans can be inhibited by sulfa drugs which prevent biosynthesis of folic acid. The dihydrofolate reductase (E.C. 1.5.1.3) inhibitors aminopterin and methotrexate also exhibit anticandidal activity, but trimethoprim does not. Kinetic evaluations with C. albicans dihydrofolate reductase indicate that methotrexate and aminopterin are tight-binding inhibitors whereas trimethoprim binds poorly.

Aminopterin↗
PubMed1982

Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria.

Azthreonam (SQ 26,776) is a synthetic monocyclic beta-lactam antimicrobial agent belonging to the monobactam family (Sykes et al., Nature [London] 291:489-491, 1981), members of which are characterized by having the 2-oxoazetidine-1-sulfonic acid moiety. Azthreonam exhibits a high degree of stability to beta-lactamases and is specifically active against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against these organisms was in general equal or superior to that observed with the third-generation cephalosporins, cefotaxime and ceftazidime. Like penicillins and cephalosporins, azthreonam interacts with essential penicillin-binding proteins of gram-negative bacteria. Azthreonam protected mice against experimental infections produced by a range of gram-negative bacteria, exhibiting efficacy comparable to that of cefotaxime and ceftazidime.

Animals↗
PubMed1982

Biosynthesis of monobactam compounds: origin of the carbon atoms in the beta-lactam ring.

The biosynthesis of monobactams by strains of Chromobacterium violaceum, Acetobacter sp., and Agrobacterium radiobacter was studied. Monobactams were produced during logarithmic growth by C. violaceum and Acetobacter sp. and during late log growth on glycerol and in stationary phase by A. radiobacter. The addition of various amino acids failed to significantly stimulate monobactam production in any of the producing organisms. Several 14C-amino acids and pyruvate were incorporated in vivo into monobactams. Serine, glycine, and cysteine were better incorporated than alanine or aspartate, whereas an excess of nonradioactive serine depressed the incorporation of labelled cysteine, glycine, and pyruvate. A comparison of [1-14C] glycine and [2-14C] glycine incorporation data suggests that glycine was first converted to serine. With a mixture of [U-14C[serine and [3-3H]serine, C. violaceum synthesized a monobactam with a complete retention of tritium, whereas with a [U-14C] cystine and [3-3H] cystine mixture, there was an extensive loss of C-3 tritium. Acetobacter sp. and A. radiobacter also utilized the double-labeled serine without the loss of tritium in their respective monobactams. It appears, therefore that in the three organisms, the carbon atoms of the beta-lactam ring of the monobactam are derived directly from serine without the loss of the C-3 hydrogen atoms, probably by an SN2 ring closure mechanism. With [methyl-14C] methionine, most of the radioactivity in the monobactam from Acetobacter sp. was in the methyl moiety of the beta-lactam ring methoxyl group.

Aztreonam↗
PubMed1982

Mode of action of azthreonam.

Azthreonam (SQ 26,776) is a member of a new class of monocyclic beta-lactam antibiotics. In Escherichia coli, azthreonam caused filamentation at its lowest effective concentration (0.2 microgram/ml), a morphological effect identical to that observed with cephalothin. The penicillin-binding protein (PBP) profile indicated a very high affinity for PBP3 (complete binding at 0.1 microgram/ml), a moderate affinity for PBP1a (complete binding at 10 micrograms/ml), and poor affinities for PBP1b, PBP2, PBP4, and PBP5/6 (complete binding at greater than or equal to 100 micrograms/ml). Accordingly, azthreonam had poor activity against Streptomyces R61 DD-carboxypeptidase (50% inhibition, greater than 100 micrograms/ml) and E. coli peptidoglycan transpeptidase (50% inhibition, 100 micrograms/ml). Azthreonam also showed very high affinity for PBP3 (complete binding at 0.1 microgram/ml) in Proteus vulgaris, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In all four organisms, its PBP profile was similar to that observed in E. coli. It is concluded that azthreonam, although of novel structure, has a mode of action similar to that of cephalosporins, affecting specifically septation in E. coli and most likely other gram-negative bacteria.

Anti-Bacterial Agents↗
PubMed1982

Interaction of azthreonam and related monobactams with beta-lactamases from gram-negative bacteria.

Monobactams containing 3 beta-aminothiazolyl oxime side chains (SQ 81,377, SQ 81,402, azthreonam, and SQ 26,917) have poor affinities for the broad-spectrum beta-lactamases TEM-2 and K1. Addition of a 4-methyl substituent significantly increased stability to hydrolysis by these enzymes. P99 cephalosporinase from Enterobacter cloacae was strongly inhibited by the monobactams. Interaction of azthreonam with the P99 enzyme in equimolar concentrations resulted in a single covalent complex which retained less than 3% catalytic activity. On incubation, enzymatic activity was slowly regained. Chromatographic studies of the incubation mixtures revealed the presence of a single ring-opened product. It is concluded that monobactams act as poor substrates for broad-spectrum beta-lactamases and tight-binding competitive substrates for the P99 beta-lactamase.

Anti-Bacterial Agents↗