Chemical modification of erythromycins. III. In vitro and in vivo antibacterial activities of new semisynthetic 6-O-methylerythromycins A, TE-031 (clarithromycin) and TE-032.

Abstract

The in vitro and in vivo antibacterial activities of6-0-methylerythromycin A (TE-03 1 , A-56268, or clarithromycin) and 6, 1 1-di-O-methylerythromycin A (TE-032) have been compared with those of erythromycin A (EM) andjosamycin (JM). TE-03 1 and TE-032, having the same antibacterial spectra as EM,are active against aerobic Gram-positive bacteria, someGram-negative bacteria, anaerobic bacteria, L-form bacteria and Mycoplasma pneumoniae. The activity of TE-03 1 against clinical isolates is equal to or two times more potent than that of EM,whereas TE-032is slightly less active than EM. The activities of TE-031 and TE-032 are pH dependent (more active at pH 8 than at 5) and are increased by adding serum to medium. TE-031 and TE-032 show dose-related bactericidal activities against Haemophilusinfluenzae. The therapeutic efficacies of TE-03 1 and TE-032against systemic and subcutaneous infections provoked by Gram-positive bacteria in mice are 4-to 35-fold superior to those of EMand JM. TE-031 and TE-032 have demonstrated higher and longer-lasting plasma levels than EMwhen administered orally to mice, rats or dogs.Erythromycin A (EM) has been a clinically useful macrolide antibiotic for over three decades. EM is particularly effective against most Gram-positive bacteria; some Gram-negative bacteria, including Neisseria, Bordetella, Brucella, Campylobacter and Legionella; and Treponema, Chlamydia and Mycoplasma. 1'2) One of limitations of EMis poor absorption after po administration because of its lability at gastric pH.6-0-Methylerythromycin A (TE-03 1 , clarithromycin) and 6, 1 1 -di-O-methylerythromycin A (TE-032) are new semisynthetic macrolides prepared by the first chemical modification3) on the C-6 hydroxyl group of EM;they are more stable to acid than EM.4) In this paper we describe the antibacterial activities ofTE-031 and TE-032 which are compared with those of EM and josamycin (JM) in vitro and in vivo. Additionally, the pharmacokinetic profiles of these compounds in several species of animals are presented. Materials and Methods Bacterial StrainsClinically isolated strains (198 strains) used in this study were obtained from several Japanese hospitals. The other strains (80 strains) were from the Taisho culture collection and ATCCstrains.Antibacterial Agents TE-031 and TE-032 were prepared at Taisho Pharmaceutical Co., Ltd. EMand JM were obtained from Abbott Laboratories and YamanouchiPharmaceutical Co., Ltd., respectively. Stock solutions of the drugs were prepared for in vitro tests by dissolving lOmg of drug in 5ml of methanol. The drugs were

Hybrid Usage of Computational Tools in Drug Synthesis

“…It is effective against most grampositive bacteria, and some gram-negative bacteria. However, it undergoes decomposition within the acidic medium of the stomach which results in undesired gastrointestinal effects [59][60][61]. To overcome the side effects, the acid stability of the macrolide is improved through modification of functional groups involved in the degradation process, which engages interactions between the hydroxyl groups at C-6 and C-12 with the carbonyl at C-9.…”

Effects of Acute and Chronic Exposure to Residual Level Erythromycin on Human Intestinal Epithelium Cell Permeability and Cytotoxicity

“…Erythromycin, a member of the macrolide antimicrobials, has been widely used in humans and animals for the treatment of a number of bacterial infections for Gram-positive cocci and Gram-negative cocci, besides mycoplasma infections [1,2]. Erythromycin exhibits antimicrobial as well as immunomodulatory properties [3,4].…”

Application of liquid chromatography/ion trap mass spectrometry to the characterization of the related substances of clarithromycin

“…Clarithromycin is a broad‐spectrum antibiotic with activity against a range of Gram‐positive and Gram‐negative organisms, atypical pathogens and some anaerobes 1–3. The in vitro activity of clarithromycin is equal to or greater than that of erythromycin A, while the in vivo antimicrobial activity has shown to be better.…”