Macrolide antibiotics in the ribosome exit tunnel: species‐specific binding and action

Abstract

Macrolide antibiotics bind in the nascent peptide exit tunnel of the ribosome and inhibit protein synthesis. The majority of information on the principles of binding and action of these antibiotics comes from studies that employed model organisms. However, there is a growing understanding that the binding of macrolides to their target, as well as the mode of inhibition of translation, can be strongly influenced by variations in ribosome structure between bacterial species. Awareness of the existence of species-specific differences in drug action and appreciation of the extent of these differences can stimulate future work on developing better macrolide drugs. In this review, representative cases illustrating the organism-specific binding and action of macrolide antibiotics, as well as species-specific mechanisms of resistance are analyzed.

Deletion of L4 domains reveals insights into the importance of ribosomal protein extensions in eukaryotic ribosome assembly

“…Macrolide antibiotics such as erythromycin disrupt translation elongation by binding to the constriction of the ribosome polypeptide exit tunnel, which is formed in part by the internal extension of L4 (Kannan and Mankin 2011). The carboxyterminal tail of L4 extends toward the A-site finger (25S rRNA helix 38) on the solvent interface via eukaryotic ribosomal components (Ben-Shem et al 2011), also suggesting its importance in eukaryotic translation.…”

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

“…Interactions are established by hydrogen bonds with specific bases at domain V of 23S rRNA, including positions A2057, A2058, A2059, C2611 (Escherichia coli numbering of 23S rRNA is used throughout the manuscript) which are common in all macrolide-ribosome interactions (Kannan & Mankin, 2011). Other positions in 23S rRNA may play a role in macrolide-ribosome interactions based on the specific macrolide considered.…”

“…Erythromycin, as well as macrolides possessing a cladinosine sugar attached to C3, also interacts with C2610 and G2505. Other macrolides, such as josamycin or carbomycin, which possess a longer disaccharide C5 side chain, also interact with positions A2451 and C2452 where the PTC-A site is located (Kannan & Mankin, 2011).…”

“…Although alterations in A2058 or A2059 affect all macrolides, most likely because these positions are directly involved in the interactions between all macrolides and ribosomes (Kannan & Mankin, 2011), substitutions like G2057A do not result in resistance to 16C macrolides, but do affect 14C macrolides (Ettayebi et al, 1985) (Table 3). Similarly, it has been shown that the C2611U alteration results in erythromycin resistance but does not affect 16C macrolides such as spiramycin or tylosin (Vannuffel et al, 1992).…”

“…Moreover, 16C macrolides such as josamycin reach the active PTC site. Thus, some authors have suggested that the lack of RluC activity may result in increased susceptibility to these macrolides (Kannan & Mankin, 2011).…”