Microbiological and pharmacokinetic studies of acyl demycinosyltylosin and related tylosin derivatives.

Abstract

A series of tylosins and acyl derivatives of 23-O-demycinosyltylosin (DMT) were initially tested for in vitro antibacterial activity and serum levels in squirrel monkeys (po) and mice (iv). Overall, the DMT compoundswere moreactive in vitro than the tylosins. Twotetraacylated DMTs,Sch 37644 and Sch 38646, were selected from the initial studies for further evaluation and compared to erythromycin and A-56268 (6-O-methyl erythromycin). Sch 37644 and Sch 38646 were 2 to 8-fold less potent in vitro against Gram-positive bacteria than erythromycin and A-56268. In squirrel monkeys, Sch 37644 (AUC, 19.7 fig-hour/ml) and A-56268 (21.6//g-hour/ml) had similar serum levels following po administration of 20 mg/kg, while Sch 38646 (1 1.8 fig à" hour/ml) and erythromycin (1.5 ,ug-hour/ml) had lower levels. In mice administered 200mg/kg orally, Sch 37644 (AUC, 19.4 fig-hour/ml) and Sch 38646 (15.4 fig-hour/ml) had higher serum levels than erythromycin (5.7 fighour/ml). A-56268 was the most active po macrolide in mouse protection studies (PD50s) against Staphylococci and Streptococci, while Sch 37644 and Sch 38646 were similar to erythromycin. 1131 Erythromycin, the most commonlyprescribed macrolide antibiotic for urinary tract and respiratory infections, has the disadvantage of being poorly absorbed after po administration. Therefore, a new series of macrolide antibiotics were prepared from tylosin and tested for improved po pharmacokinetics, as well as the retention of the good efficacy of erythromycin against Gram-positive infections. The derivatives were tested for in vitro antimicrobial activity, and pharmacokinetics in squirrel monkeys (po) and mice (iv). On the basis of initial results, two compounds were selected for further studies, 3,23,2'-triO -acetyl-23-0demycinosyl-4//^-/so-valeryltylosin (Sch 37644) and its 12,13-epoxy derivative (Sch 38646). These compoundswere compared to erythromycin and a new orally active erythromycin derivative, A-56268 (Abbott Laboratories, Abbott Park, IL). The data were presented in part at the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy0. Materials and Methods Antibiotics A series of tylosin derivatives were synthesized by Dr. Mallams in our laboratories2'3*. These derivatives consisted of two structurally related groups of compounds: Tylosin and 23-O-demycinosyltylosin (DMT) and their acyl, hydrazone, and 12,13-epoxy derivatives. The structures of the two selected derivatives, Sch 37644 and Sch 38646, are shown in Fig. 1.

Resistance to the macrolide antibiotic tylosin is conferred by single methylations at 23S rRNA nucleotides G748 and A2058 acting in synergy

“…In contrast, nucleotide A752 is not protected by macrolides such as erythromycin, carbomycin, and spiramycin, which lack a 14-[23-]sugar moiety (34,45,46), nor by the smaller lincosamide structures (47). The importance of the mycinosyl moiety of tylosin for antimicrobial activity has been demonstrated (48)(49)(50)(51).…”