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Biomedical subjects

D J Knowles

Publications and source records attributed to D J Knowles.

63 records · Page 4Linked to original sources
PubMed1990

MM 45289, a potent glycopeptide antibiotic which interacts weakly with diacetyl-L-lysyl-D-alanyl-D-alanine.

MM 45289 (A82846A, eremomycin), a glycopeptide antibiotic of the vancomycin type, was confirmed to have improved antibacterial activity over vancomycin. However its affinity (Ka) for the target site peptide mimetic diacetyl-L-lysyl-D-alanyl-D-alanine (DALAA) was 23-fold lower. Concentrations of DALAA required to reverse the antibacterial activity of MM 45289 were in the order of 10 to 50-fold higher than for vancomycin. These results have implications for both mode of action studies and mechanism-based screening strategies for this class of antibiotic.

Amino Acid Sequence↗
PubMed1989

9,11-cyclic acetal derivatives of (9S)-9-dihydroerythromycin A.

A series of 9,11-cyclic acetal derivatives of (9S)-9-dihydroerythromycin A (4) have been prepared and their antibacterial activities compared to those of erythromycin A and 9-dihydroerythromycin A. Many of the cyclic acetal derivatives showed better antibacterial activity than their parent 4. In particular, the acetaldehyde acetal (9-O,11-O-ethylidene-9-dihydroerythromycin A) (8b) showed good antibacterial activity in comparison with erythromycin A but was not sufficiently improved in vivo to warrant progression.

Cyclization↗
PubMed1989

Biological properties of ER 42859, a novel erythromycin derivative.

The antimicrobial activity of a new semi-synthetic oral erythromycin derivative, ER 42859, was evaluated in vitro and in vivo in comparison with erythromycin, spiramycin, josamycin, oleandomycin and the newer semi-synthetic derivatives flurithromycin, roxithromycin and A-56268. MIC values of ER 42859 were superior to those of roxithromycin, oleandomycin, josamycin and spiramycin but generally 2-fold poorer than those of erythromycin. The activity equalled that of erythromycin against Haemophilus influenzae and was superior to that of roxithromycin and A-56268 against this organism. MIC values of the compound were greatly influenced by pH due to the dibasic nature of the molecule. ER 42859 had markedly superior activity to erythromycin, spiramycin, josamycin, oleandomycin and flurithromycin against experimental infections in mice and similar activity to roxithromycin and A-56268. Blood and tissue levels were high and prolonged in rodents. In volunteers, blood levels were prolonged but inferior to those of erythromycin.

Animals↗
PubMed1988

Uptake of erythromycin by McCoy and HEp2 cells: its dependence on cellular pH gradients.

The accumulation of erythromycin, a weak lipophilic base, was studied in two mammalian cell lines. Uptake was similar in both cell types, being highly pH dependent and not saturated even at external concentrations of 1000 mg/l. At pH 6.7 the ratio of cellular:extracellular erythromycin concentrations (C/E) was only 2.0, whereas at pH 7.5 it was as high as 7.0. Carbonylcyanide-m-chlorophenyl hydrazone, an uncoupler of oxidative phosphorylation which was used to collapse cellular pH gradients, caused a 50% reduction in C/E ratio within five minutes when the external pH was greater than 6.9 but had no effect at or below pH 6.7. These results suggest that ion-trapping plays a major role in the accumulation of erythromycin by these cells.

Cell Line↗
PubMed1988

Erythromycin A 11,12-methylene acetal.

Erythromycin A 11,12-methylene acetal (5) and the corresponding 9-methoxime, 9-dihydro, and 8-hydroxy derivatives have been prepared and their antibacterial activities compared with those of erythromycin A and its 11,12-cyclic carbonate. The simple methylene acetal 5 showed excellent activity against Gram-positive organisms in vitro.

Erythromycin↗
PubMed1984

A simple rapid technique to measure neutrophil or serum bactericidal activity.

A rapid and simple technique to measure both serum and neutrophil bactericidal activity is described. It is based on microtitre equipment and avoids the cumbersome and time consuming serial dilution and plate counting of conventional experiments. A constant concentration of neutrophils and/or serum is incubated with a series of dilutions of bacterial suspensions. Bacterial survival is estimated at various times from their ability to form colonies on agar and the results conveniently expressed as the largest bacterial population that can be eliminated by either neutrophils or serum alone. The technique is as simple and quick as a standard microtitre MBC test commonly used for antibiotics and scoring of the results takes only a few seconds per sample. Data are presented showing the close correlation between results obtained using this technique and those from conventional tests of neutrophil bactericidal activity and phagocytosis-associated chemiluminescence.

Animals↗
PubMed1978

The chemotactic response of plasmodia of the myxomycete Physarum polycephalum to sugars and related compounds.

A new technique, the double strip method, for studying the chemotaxis of myxomycete plasmodia is described. Physarum polycephalum was attracted by the aldohexoses D-glucose, D-galactose and D-mannose and their derivatives 2-deoxy-D-glucose and maltose, thresholds ranging from 0.25 mM (D-glucose) to 5 mM (D-mannose). These sugars competed with each other, a uniform background of one of them inhibiting taxis to the others. Other attractants were N-acetyl-D-glucosamine and mannitol, with thresholds at 1 mM, and fucose (6-deoxy-D-galactose). Although in general only those carbohydrates which could support growth were attractants, there were exceptions such as 2-deoxy-D-glucose; hence metabolism of a compound was not necessary for attraction. In addition, some compounds, such as fructose, could be metabolized but did not attract. At high concentrations (about 100 mM) all the compounds tested, including attractants, could under appropriate conditions cause repulsion, probably through osmotic effects.

Acetylglucosamine↗
PubMed1978

Growth and migration of plasmodia of the myxomycete Physarum polycephalum: the effect of carbohydrates, including agar.

A method for studying the growth and migration of myxomycete plasmodia on the surface of agar and other gels was devised. The migration rate of plasmodia of Physarum polycephalum was greatly reduced when nutrients that permit rapid growth were present, and slightly reduced by most sugars tested at 56 mM, including some that were not utilized. The carbohydrate requirement of the myxomycete could be satisfied by a range of sugars and derivatives, including mannitol and agar, utilization of the latter being slight but definite. Fructose could be utilized as long as it was not the sole carbohydrate present.

Agar↗