Ronald Andrew Lemahieu

Induction of Erythromycin Resistance in Staphylococcus aureus by Erythromycin Derivatives

The ability of 53 erythromycin analogues to induce resistance to erythromycin in Staphlococcus aureus was evaluated. Only derivatives with antibacterial activity induced resistance, although some antibacterial compounds did not induce resistance. No derivatives without antibacterial activity but with ability to induce resistance were found.

Inhibition of [14C]Chloramphenicol Binding to Escherichia coli Ribosomes by Erythromycin Derivatives

The effect of erythromycin A and 35 analogues of erythromycin A on [14C]chloramphenicol binding to Escherichia coli ribosomes was evaluated. Substitutions on various portions of the erythromycin molecule were made with retention of ability to bind to ribosomes. Specifically, substantial activity in interference with [14C]chloramphenicol binding was retained upon removal of the cladinose and various substitutions on the 3-hydroxyl, the oxime, and 2-hydroxyl groups. Erythromycin analogues with relatively poor binding activity to ribosomes could be detected. This assay can be used alone or in conjunction with microbiological assays for screening of active analogues. It permits an estimate of the general binding activity of compounds rapidly and directly. The assay reflects the ability of the compounds to interact with their target organelle, the ribosome, and may serve as a useful adjunct in developing new compounds.

Correlation of Effects of Erythromycin Analogues on Intact Bacteria and on [14C]Erythromycin Binding to Escherichia coli Ribosomes

The dissociation constants for binding to ribosomes from Escherichia coli and concentrations at which 50% inhibition of [14C]erythromycin binding to ribosomes occurred were determined for 45 erythromycin analogues. These values were correlated with their antibacterial activities against Bacillus subtilis. Compounds which bound to ribosomes best showed the greatest activities; those which were poorly bound to ribosomes showed little or no antibacterial activity. The ribosomal binding assays therefore reflected the general antibacterial potential of the erythromycin analogues.

Fluorescent Assay for Estimating the Binding of Erythromycin Derivatives to Ribosomes

A fluorescent erythromycin derivative was used to determine the binding of erythromycin derivatives to ribosomes. The assay is rapid, sensitive, and convenient. Because measurements are made in solution, they represent equilibrium conditions, unlike filter binding assays which perturb the equilibrium. Results correlate well with measurements made by other techniques.

4-[5-(2,3-dihydroxyphenyl)pentyloxy]-2-hydroxy-3-propylbenzoic acid (Ro 24-0553): an orally active 5-lipoxygenase inhibitor with antiinflammatory activity

The chemical synthesis and pharmacological properties of 4-[5-(2,3-dihydroxyphenyl)pentyloxyl]-2-hydroxy-3-propylbenzoic acid (Ro 24-0553, 1), a novel 5-lipoxygenase (5-LO) inhibitor with in vivo activity appropriate for development as a therapy for inflammatory bowel disease, are described