Mechanistic Insights into Clinically Relevant Ribosome-Targeting Antibiotics

Abstract

Antibiotics targeting the bacterial ribosome are essential to combating bacterial infections. These antibiotics bind to various sites on the ribosome, inhibiting different stages of protein synthesis. This review provides a comprehensive overview of the mechanisms of action of clinically relevant antibiotics that target the bacterial ribosome, including macrolides, lincosamides, oxazolidinones, aminoglycosides, tetracyclines, and chloramphenicol. The structural and functional details of antibiotic interactions with ribosomal RNA, including specific binding sites, interactions with rRNA nucleotides, and their effects on translation processes, are discussed. Focus is placed on the diversity of these mechanisms and their clinical implications in treating bacterial infections, particularly in the context of emerging resistance. Understanding these mechanisms is crucial for developing novel therapeutic agents capable of overcoming bacterial resistance.

Keywords: antibiotics; protein biosynthesis; ribosome.

Figure 1

Antibiotics actions during protein synthesis.

Figure 2

The location of adenine residues when the A-site is unoccupied by any aa-tRNA (A-site free); when cognate aa-tRNA is bound to the A-site (cognate tRNA), which causes the flipping out of residues A1492 and A1493; and finally, when binding of paromomycin artificially flips out residues A1492 and A1493. PDB accession numbers are as follows: 1J5E (A-site free) [21], 1IBM (cognate tRNA) [28], and 1IBL (paromomycin) [28]. Green—adenine residues, red—anticodon stem-loop of the cognate tRNA, purple—paromomycin molecule.

Figure 3

The binding site of tetracycline. Left panel: A, P, and E functional sites (grey—rRNA, blue—tetracycline, green—tetracycline-interacting rRNA). Right panel: tetracycline shown in blue; surrounding rRNA demonstrated in green (PDB accession no. 1I94).