Macrolide myths

Abstract

In spite of decades of research, our knowledge of the mode of interaction of macrolide antibiotics with their ribosomal target and of the mechanism of action of these drugs remain fragmentary. Experimental facts obtained over the past several years question some of the concepts that were viewed as a 'common knowledge'. This review focuses on certain aspects of binding and action of macrolides that may need re-evaluation in view of the new findings.

Figure 1

Chemical structures of macrolide antibiotics, inhibitors of protein synthesis. The major representatives of clinically-relevant classes of macrolide antibiotics are shown and structural elements relevant to the subject of the review are indicated.

Figure 2

The nascent peptide exit tunnel. 3’ ends of aminoacyl- and peptidyl-tRNAs converge in the peptidyl transferase center where assembly of amino acids into a polypeptide takes place. The nascent peptide traverses the body of the large ribosomal subunit through the exit tunnel whose outside surface is shown in yellow and inside surface is shown in blue. The tunnel walls are formed primarily by segments of rRNA but extended loops of ribosomal proteins L4 and L22 reach the tunnel near its constriction close to where the macrolide binding site is located. The location of the peptidyl transferase center and of the macrolide binding site near the tunnel constriction are indicated. Reproduced with minor changes from [36].

Figure 3

Interactions of macrolides with the ribosome. Erythromycin (red) and tylosin (purple) are shown within their binding sites in the H. marismortui large ribosomal subunit [9,10]. A2451 which marks the location of the peptidyl transferase active site (PTC) is shown in green. Nucleotide residues A2058 and A2059 involved in interactions with desosamine sugar of erythromycin or mycaminose-mycarose disaccharide of tylosin (A2058 and A2059) are shown in cyan. U752 in H. marismortui (A752 in most pathogenic bacteria) interacting with the mycinose sugar of tylosin and likely involved in interactions with alkyl-aryl side chains of ketolides in some bacteria is shown in violet. Loops of ribosomal proteins L4 and L22 approaching the macrolide binding site are shown in beige.

Figure 4

Different orientation of the alkyl-aryl side chain (indicated by magenta triangle) of telithromycin bound to the D. radiodurans (left) or H. marismortui (right) large ribosomal subunit.

Figure 5

The bound molecule of erythromycin leaves sufficient space in the exit tunnel for the nascent peptide to squeeze by. The 9 amino acid-long nascent peptide (fMG-I-F-S-I-F-V-I) encoded in the ermCL regulatory ORF was modeled in the exit tunnel of the H. marismortui large ribosomal subunit complexed with erythromycin [10,24]. The erythromycin molecule is shown in red, the nascent peptide is shown in a space-fill representation in olive and CCA end of peptidyl-tRNA in the ribosomal P site is shown as balls-and-sticks (light-green). The A2062 residue of 23S rRNA, which needs to lie flat against the tunnel wall in order to let the nascent peptide slide by the bound macrolide molecule, is shown in blue.