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Biomedical subjects

K Bush

Publications and source records attributed to K Bush.

At least 109 records · Page 6Linked to original sources
PubMed1987

Improved sensitivity in assays for binding of novel beta-lactam antibiotics to penicillin-binding proteins of Escherichia coli.

Tigemonam and temocillin, but not aztreonam, bound to penicillin-binding proteins (PBPs) 1a and 3 of Escherichia coli with apparent improved affinity when challenged with benzylpenicillin at lowered temperatures. Half times for deacylation of the tigemonam-PBP complexes were shorter than were those of the corresponding aztreonam-PBP complexes. The implications of the routine testing of PBP affinities are discussed.

Anti-Bacterial Agents↗
PubMed1986

Properties of a class C beta-lactamase from Serratia marcescens.

A beta-lactamase produced by a penicillin-resistant strain of Serratia marcescens was isolated and purified. The kcat. value for benzylpenicillin was about 5% of that observed for the best cephalosporin substrates. However, the low Km of the penam resulted in a high catalytic efficiency (kcat./Km) and the classification of the enzyme as a cephalosporinase might not be completely justified. It also exhibited a low but measurable activity against cefotaxime, cefuroxime, cefoxitin and moxalactam. Substrate-induced inactivation was observed both with a very good (cephalothin) or a very bad (moxalactam) substrate. The active site was labelled by beta-iodopenicillanate. Trypsin digestion produced a 19-residue active-site peptide whose sequence clearly allowed the classification of the enzyme as a class C beta-lactamase.

Amino Acids↗
PubMed1986

Evaluation of enzyme inhibition data in screening for new drugs.

Enzyme inhibitors selected from either natural product screening or synthetic chemistry programmes can be characterized according to a number of criteria to determine their usefulness as potential drug candidates. Inhibition may be classified as either irreversible or reversible. Irreversible inhibitors may be described with respect to first order rate constants or half-times for inactivation. Reversible inhibitors should be evaluated with respect to Ki values rather than I50 values. Assays should be designed using the simplest and most precise procedures available. If possible, assays utilizing continuously-recording methods should be selected. When reversible inhibitors are desired, greater sensitivity for inhibition is achieved using low substrate concentrations. For irreversible inhibitors or tight-binding competitive inhibitors, low enzyme concentrations also result in greater inhibitory sensitivity. The order of addition of enzyme and substrate should be varied to determine whether inhibition requires preincubation of enzyme and inhibitor for maximum effect. Time-dependence of inhibition should also be established. Enzyme inhibitors should be specific for the enzyme that is being targeted. Novel competitive inhibitors of angiotensin-converting enzyme were isolated in the author's laboratory using the above philosophy of screening for enzyme inhibitors. The properties of the muraceins, phenacein and aspergillomarasmine A' are discussed.

Acetylcholinesterase↗
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↗
PubMed1985

Two new inhibitors of phospholipase A2 produced by Penicillium chermesinum. Taxonomy, fermentation, isolation, structure determination and biological properties.

Plastatin and the known fungal metabolite, luteosporin, have been isolated from fermentations of Penicillium chermesinum as inhibitors of porcine pancreatic phospholipase A2 (PLA2). Structure 1 for plastatin was deduced from its spectroscopic properties. Plastatin and luteosporin inhibited pancreatic PLA2 competitively with Ki values of 0.89 microM and 12.8 microM, respectively. PLA2 preparations from Naja naja and Crotalus adamanteus were not significantly inhibited by plastatin and luteosporin.

Chemical Phenomena↗
PubMed1984

Phenacein--an angiotensin-converting enzyme inhibitor produced by a streptomycete. I. Taxonomy, fermentation and biological properties.

Phanacein, 3,6-dihydroxy-1-phenazinecarboxylic acid, was a specific angiotensin-converting enzyme (ACE) inhibitor isolated from a member of the Streptomyces tanashiensis-zaomyceticus group. Phenacein acted as a pure competitive inhibitor with a Ki of 0.58 microM. ACE inhibition could be reversed by Zn++, but not by Co++, Ca++, or Mg++; therefore, phenacein may chelate the active site zinc of ACE. However, other zinc-containing enzymes were not inhibited at high phenacein concentrations. Phenacein exhibited weak activity against Gram-positive bacteria, but was not active against Candida sp. or Gram-negative organisms.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Muraceins--muramyl peptides produced by Nocardia orientalis as angiotensin-converting enzyme inhibitors. I. Taxonomy, fermentation and biological properties.

Three muraceins , a family of muramyl peptides, were isolated from Nocardia orientalis as inhibitors of angiotensin-converting enzyme (ACE). Muracein A, the most potent inhibitor, inhibited ACE competitively with a Ki of 1.5 microM. Liver alcohol dehydrogenase and carboxypeptidase A, two other zinc-containing enzymes, were not inhibited at 150 microM. Inhibition of ACE could not be reversed by divalent cations.

Acetylmuramyl-Alanyl-Isoglutamine↗
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↗
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

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↗
PubMed1982

Solute effects on the mechanical properties of arterial elastin.

We have examined the effects of various solutions (SDS, DMSO, NaCl) on the swelling and mechanical properties of arterial elastin. Our results indicate that SDS-swollen elastin is stiffer, stronger, and appears to fail at smaller extensions than water-swollen elastin. In order to determine if these changes in mechanical properties are due to swelling changes or to a specific effect of SDS bound to the elastin network, we studied the effect of DMSO on the mechanical properties of elastin. DMSO swells elastin to the same extent as 0.1 M SDS, but DMSO is uncharged and probably does not interact directly with the elastin protein. The data for DMSO-swollen elastin corrected for swelling changes are virtually identical to those of water-swollen elastin but significantly different from those of SDS-swollen elastin. Thus, there is apparently a specific SDS effect, and this effect probably arises from the high negative charge density due to bound SDS. Lastly, studies of changes induced by sodium chloride concentrations in the physiological range indicate that there is no significant change in stiffness, strength, or extensibility due to increased NaCl levels.

Animals↗
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↗