Mode of action of macrolides

Role of protonated and neutral forms of macrolides in binding to ribosomes from gram-positive and gram-negative bacteria

“…We (12) demonstrated that the ability of erythromycin to inhibit in vitro protein synthesis by ribosomes isolated from S. aureus increases with increasing pH. Mao and Weigand concluded that only the neutral form of macrolide efficiently inhibited protein synthesis.…”

“…Initial efforts were directed towards determination of its mode of action and efficacy in clearing bacterial infections. These early investigations showed that erythromycin was a very safe and effective agent for treating infection due to susceptible bacteria and that its mode of action involved binding to bacterial 50S ribosomal subunits (11,13) with resultant perturbation of protein synthesis (1,12). Although the details regarding perturbation of ribosome function are still not entirely understood, binding to a single site on the 50S ribosomal subunit has been firmly established by independent analysis (7-10, 13, 20).…”

“…Determining whether the protonated or neutral form of erythromycin, or both, binds to the 50S ribosomal subunit is important not only for the analysis of interaction kinetics, but also for understanding the mode of action of erythromycin. If both forms bind, one must consider the possibility that each causes a different perturbation of ribosome function, a possibility that has apparently been considered only once in the literature (12). That study revealed a strong correlation between pH and potency of inhibition of in vitro protein synthesis for the basic macrolides erythromycin and oleandomycin, ranging from a stimulation of protein synthesis below pH 7 to progressively increasing inhibition of protein synthesis up to pH 8.5.…”

Recovery of Escherichia coli IFO3301 Injured by Glycine and Ethanol.

“…These antibacterial agents show different bacterostatic actions. The former inhibits transpeptidation after aminoacyl t-RNA synthesis in cells (Mao & Wiegand, 1968), while the latter inhibits electron transport and H + -ATPase in cells (Noumi et al, 1987). Considering these results, inhibition of bacterial growth by a combination of Gly and Et would be due to suppression of protein synthesis and respiratory electron transport.…”

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

“…In addition, we also determined the association constants for the binding of various erythromycin analogues to ribosomes. Since erythromycin is an effective antibiotic because of its inhibition of protein synthesis through binding to the large subunit of bacterial ribosomes (3,4,7), it was therefore of interest to determine if the in vitro activity of the analogues was related to the association constants we determined in cell-free extracts. In this communication, we report the relative activity of the erythromycin analogues in cell-free extracts compared with their activity on intact bacteria.…”