PubMed Health⌕ Search

Biomedical subjects

D P Bonner

Publications and source records attributed to D P Bonner.

At least 55 records · Page 3Linked to original sources
PubMed1985

Resistance caused by decreased penetration of beta-lactam antibiotics into Enterobacter cloacae.

Strains of Enterobacter cloacae were selected on the basis of resistance to aztreonam, ceftazidime, moxalactam, or imipenem. All strains produced the same E2 beta-lactamase, with an isoelectric point greater than 9.5 and with high hydrolytic activity in the presence of cephaloridine. Resistance to beta-lactams could not be correlated with the amount of beta-lactamase present in the various strains. beta-Lactamase activity was induced strongly by moxalactam and imipenem in the wild-type and moxalactam-resistant strains, with beta-lactamase representing as much as 4% of the total cellular protein after induction (2 X 10(5) molecules per cell). Ceftazidime and aztreonam were poor inducers. None of the antibiotics studied was readily hydrolyzed by the E2 beta-lactamase; aztreonam and moxalactam inhibited the enzyme with apparent Ki values of 1.2 and 100 nM, respectively. Aztreonam, which bound covalently to the E2 beta-lactamase with a half-life of 2.3 h at 25 degrees C, was used to measure penetrability of beta-lactam into the periplasmic space of the resistant E. cloacae strains. In all of the E2-producing organisms studied, a significant permeability barrier existed. A maximum concentration of 0.02 microgram of aztreonam per ml should have saturated the periplasmic beta-lactamase in the highest enzyme producers studied. However, fully active beta-lactamase was observed in the periplasm of cells exposed to aztreonam at concentrations at least 1,000-fold higher than that theoretically necessary to inhibit the total enzyme within the cell. Thus, the major cause for resistance to beta-lactam antibiotics in these E. cloacae strains was lack of penetration across the outer membrane.

Anti-Bacterial Agents↗
PubMed1984

Structure activity relationships among the monobactams.

The monobactam nucleus (3-AMA) exhibits weak antibacterial activity and thus, as with the penicillins and cephalosporins, molecular substitution around the central nucleus is essential to realize the antibacterial potential of these molecules. Side chain structure/activity relationships in monobactams parallel those of the penicillins and cephalosporins. Such a relationship is not unexpected in view of the common enzymatic targets shared by these structurally divergent types. Side chain substitution of the monobactam nucleus leads to compounds exhibiting primarily Gram-positive, primarily Gram-negative or broad-spectrum activity. However, incorporation of small polar groups (amino, hydroxyl, carboxylic or sulphonic) at the alpha position of these side chains leads to poorly active compounds. This observation is the most striking divergence between monobactam and penicillin/cephalosporin structure-activity relationships. The most striking gain in anti-bacterial activity is observed with the introduction of an aminothiazoleoxime side chain as the 3-acyl substituent. In the case of carbonyl-activated and phosphate activated compounds, there is total reliance on this side chain grouping for achieving activity. Activity against Gram-positive bacteria, if present, is closely related to the nature of the acyl side chain. The aminothiazoleoxime side chains characteristically reduce activity against this organism class. Substitution at the 4-position of the monocyclic ring although capable of producing dramatic changes in biological activity, is highly unpredictable. In the SO3-activated molecules 4-substitution is essential for beta-lactamase stability and in many instances results in increased intrinsic activity of the molecule. Incorporation of 4-substituents on the beta-lactamase susceptible O-activated molecules has little or no effect on beta-lactamase stability or antibacterial activity. In the case of carbonyl- and phosphate-activated species, while offering no advantages, 4-substitution in many instances is highly deleterious to the activity of the molecule. The 'activating' group on the beta-lactam nitrogen, responsible for the activation of the beta-lactam ring can be varied quite widely while retaining high intrinsic activity. The O-activated compounds although showing the potential for broad-spectrum activity are beta-lactamase unstable, while the beta-lactamase stable compounds tend to show preferential activity against Gram-negative rods. There can be little doubt that additional activating groups will be incorporated on the monocyclic beta-lactam ring and it will be interesting to see what additional properties can be achieved by this approach.

Anti-Bacterial Agents↗
PubMed1983

Prediction of aztreonam pharmacokinetics in humans based on data from animals.

Interspecies correlations of pharmacokinetic parameters obtained in animals were used to predict human pharmacokinetics in order to design the first clinical study of an investigational drug. The serum pharmacokinetics of aztreonam, a novel monocyclic beta-lactam antibiotic, were described for mice, rats, rabbits, and monkeys, using serum clearance and apparent volume of distribution. A one-compartment pharmacokinetic model yielded predictions for aztreonam clinical pharmacokinetics that were very helpful in choosing doses and serum sampling times for the first kinetic study in healthy male volunteers. Predicted serum aztreonam concentrations agreed well with subsequently measured values in man.

Animals↗
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

Penicillin-binding proteins in a Staphylococcus aureus strain resistant to specific beta-lactam antibiotics.

The penicillin-binding proteins (PBPs) of a clinical isolate of Staphylococcus aureus specifically resistant to oral cephalosporins were compared with those of a susceptible strain. In the resistant strain, PBP3 (75,000 molecular weight) was missing or had substantially (greater than 100-fold) reduced affinity for penicillin; PBP2 (80,000 molecular weight) was increased in amount and contained a satellite band, PBP2'; PBPs 1 and 4 were unchanged. Oral cephalosporins bound poorly to PBP2 in both susceptible and resistant strains, but only in the latter did binding correlate with antibiotic activity. The results are consistent with the suggestion that PBP2 is essential in S. aureus. PBP2 might in addition compensate for PBP3 when the latter is missing. In the susceptible strain the lack of correlation between binding to PBP2 and beta-lactam antibiotic activity is due to the very high affinity of the also essential PBP3 for beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed1982

SQ 26,180, a novel monobactam. I Taxonomy, fermentation and biological properties.

Strains of Chromobacterium violaceum, isolated from various environments, were found to produce a novel monocyclic beta-lactam antibiotic. The antibiotic, SQ 26,180 was weakly active against Gram-positive and Gram-negative bacteria with the exception of mutants hypersensitive to beta-lactam antibiotics. The compound was highly stable to beta-lactamases and acted as an inhibitor of the P99 enzyme from Enterobacter cloacae. SQ 26,180 showed affinity for penicillin-binding proteins 1a, 4 and 5/6 of Escherichia coli and inhibited R61 DD-carboxypeptidases.

Anti-Bacterial Agents↗
PubMed1982

Distribution of beta-lactam and beta-lactone producing bacteria in nature.

Over one million bacteria were isolated from a large variety of soil, plant and water samples collected from different environments and examined in an extremely sensitive and highly specific screen for beta-lactam production. A group of seven related monocyclic beta-lactams (monobactams) were isolated from strains representing four genera-Agrobacterium, Chromobacterium, Gluconobacter and Pseudomonas. Monobactam-producing strains of Agrobacterium and Pseudomonas were isolated only rarely. Producing strains of Chromobacterium were isolated from a relatively limited number of habitats while the Gluconobacter strains appeared to be widespread in nature. In addition, three closely related beta-lactone-containing molecules were isolated from strains representing three genera-Arthrobacter, Bacillus and Pseudomonas. The Bacillus and Pseudomonas strains were isolated infrequently but from a variety of samples. The producing strain of Arthrobacter was isolated only once.

Anti-Bacterial Agents↗
PubMed1981

Absence of cholesterogenesis regulation in the liver and prostate of the BIO 87.20 hamster.

Normal, adult golden Syrian hamsters and the inbred stain BIO 87.20 Syrian hamsters were maintained on either control, cholesterol, candicidin or clofibrate diets for time periods of up to 4 months. The ventral prostate gland in both species was found to synthesize cholesterol at a greater rate than the liver. Also, our results show that, while hepatic cholesterol synthesis in the normal Syrian hamster is under feedback control with dietary cholesterol, hepatic cholesterol synthesis in the BIO 87.20 hamster, and prostatic cholesterol synthesis in either species, is under no such control. This apparent regulatory defect in the BIO 87.20 hamster, which results in a dramatic accumulation of cholesterol in the liver and serum, renders this animal a potentially valuable in vivo model for the study of cholesterol-related disorders.

Animals↗
PubMed1981

Siderochelin, a new ferrous-ion chelating agent produced by Nocardia.

A new ferrous-ion chelating agent, siderochelin, was isolated from fermentation broths of Nocardia sp. SC 11,340. Siderochelin was produced by conventional submerged culture and purified by solvent extraction and recrystallization. The antibiotic was crystallized from acetonitrile as a mixture of diastereoisomers. The molecular formula of siderochelin was determined as C11H13N3O3 on the basis of elemental analysis and mass spectrometry, and the structure was elucidated by X-ray crystallography. The compound shows a broad spectrum of antimicrobial activity, being active against bacteria, fungi and protozoa.

Anti-Bacterial Agents↗
PubMed1980

Izumenolide-a novel beta-lactamase inhibitor produced by Micromonospora. II. Biological properties.

Izumenolide is a potent inhibitor of beta-lactamases, especially from Gram-negative bacteria. The I50 value of 0.01 microgram/ml for TEM-2 beta-lactamase, after 10 min preincubation, corresponds to a ratio of 7.6 moles inhibitor per mole of enzyme. The initial inhibitory reaction with TEM-2 beta-lactamase exhibits mixed reaction kinetics, suggesting a possible overlapping binding site with the active center. Tem-2 beta-lactamase is irreversible inactivated by izumenolide in a biphasic reaction. Carbenicillin offers partial protection against inactivation. Izumenolide exhibits limited antibiotic activity against some Gram-negative bacteria. Against beta-lactamase producing bacteria izumenolide provides protection to ampicillin and cephaloridine but the protection is limited due to permeability problems associated with izumenolide entry into the cells.

Animals↗
PubMed1976

The effect of fetal bovine serum on polyene macrolide antibiotic cytotoxicity and antifungal activity.

The relationships between fetal bovine serum (FBS) concentration and polyene macrolide antibiotic cytotoxicity to animal cells and to fungi were evaluated. The toxicity of amphotericin B (AB) and its derivative, amphotericin B methyl ester (AME), toward KB cells was found to be directly related to fetal bovine serum concentration. At higher FBS levels, increased concentrations of AB and AME were required to reduce 72-hr KB viable cell numbers of 50% of control values. Similarly, polyene macrolide antibiotic levels required to inhibit the growth of Saccharomyces cerevisiae to 50% of controls, and for obtaining minimum fungicidal concentrations (MFC), were greater when higher levels of FBS were used. In addition, AME was less toxic than AB toward KB cells grown in media containing 2, 5, 10, 15 or 20% FBS, whereas the antifungal activities of AB and AME were similar. AME was also capable of eliminating Candida albicans, Saccharomyces cerevisiae, Aspergillus niger or Fusarium moniliforme from KB cultures at antibiotic levels which exhibited less cell toxicity than did the concentrations of AB required for a similar response. These findings indicate that AME may be a potentially useful antifungal antibiotic for tissue culture systems.

Amphotericin B↗