Macrolide antibiotics structure-activity relationships

Extensive early studies of in vitro and in vivo structure-activity relationships within the leucomycin family revealed correlations between the number and type of O-acyl substituents and the compounds antibacterial potency, efficacy in treating experimental infections, and serum antibiotic concentrations [26]. Consequently, esterification of all hydroxyl groups within several leucomycin-related macrolides was conducted to find derivatives with better antibiotic activity and pharmaceutical properties (such as greater water solubility and masking their extremely bitter taste). From such investigations with midecamycin, miokamycin was synthesized and characterized as a useful new macrolide antibiotic [24, 27]. It has now been commercially launched in several countries [5]. 

The 16-membered macrolide antibiotics are generally classified into two large groups, namely, the leucomycin-related family and the tylosin-related family, on the basis of the substitution patterns of their aglycons (Fig. 28) [187]. Interestingly, the leucomycin series, such as leucomycin, josamycin, midecamycin, and spiramycin, have been used clinically for humans, while the tylosin series has been utilized in veterinary medicine. In this section, we describe recent studies on the chemical modification of 16-membered macrolides and their structure-activity relationships. 

Sakakibara, H., and Omura, S. (1984). Modification and structure-activity relationship. In Macrolide Antibiotics Chemistry, Biology, and Practice (S. Omura, Ed.), pp. 85-126. Academic... 

Delaforge, M., Jaouen, M., and Mansuy, D. (1983). Dual effects of macrolide antibiotics on rat liver cytochrome P-450. Induction and formation of metabolite complexes A structure-activity relationship. Biochem. Pharmacol. 32, 2309-2318. 

These studies on modifications to erythromycin A have provided a great deal of important and interesting pharmacokinetic improvements, broadening an antibacterial spectrum and developing potency. For details, see Weisblum [183] and Bryskier et al. [207, 208]. Further work on structure-activity relationships in macrolide antibiotics with due consideration for their water solubility will provide a sufficient opportunity to improve antibacterial macrolides. 

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