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Mechanism of Action of Spiramycin and Other Macrolides

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Mechanism of Action of Spiramycin and Other Macrolides Journal of Antimicrobial Chemotherapy (1988) 22, Suppl. B, 13-23 Mechanism of action of spiramycin and other macrolides Downloaded from https://academic.oup.com/jac/article/22/Supplement_B/13/714054 by guest on 02 October 2021 a a Anne Brisson-Noel , Patrick Trieu-Cuot" and Patrice Courvalin • b aUnite des Agents Antibacteriens, CNRS UA271, Institut Pasteur, 75724 Paris Cedex 15; b National Reference Center for Antibiotics, Institut Pasteur, 75724 Paris Cedex 15, France Macrolide antibiotics constitute a group of 12 to 16-membered lactone rings substituted with one or more sugar residues, some of which may be amino sugars. They inhibit bacterial protein synthesis both in vivo and in vitro with varying potencies. Macrolides are generally bacteriostatic, although some of these drugs may be bactericidal at very high concentrations. The mechanism of action of macrolides has been a matter of controversy for some time. Spiramycin, a 16- membered macrolide, inhibits translocation by binding to bacterial 50S ribosomal subunits with an apparent I : I stoichiometry. This antibiotic is a potent inhibitor of the binding to the ribosome of both donor and acceptor substrates. Spiramycin induces rapid breakdown of polyribosomes, an effect which has formerly been interpreted as occurring by normal ribosomal run-off followed by an antibiotic­ induced block at or shortly after initiation of a new peptide. However, there is now convincing evidence that spiramycin, and probably all macrolides, act primarily by stimulating the dissociation of peptidyl-tRNA from ribosomes during translocation. Although the ribosomes of both Gram-positive and Gram-negative organisms are susceptible to macro Ii des, these antibiotics are mainly used against Gram-positive bacteria since they are unable to enter the porins of Gram-negative bacteria. Resistance to macrolides in clinical isolates is most frequently due to post­ transcriptional methylation of an adenine residue of 23S ribosomal RNA, which leads to co-resistance to macrolides, lincosamides and streptogramins type B (the so-called MLSB phenotype). Other mechanisms of resistance involving cell impermeability or drug inactivation have been detected in Staphylococcus spp. and Escherichia coli. These strains are resistant to 14-membered macrolides (erythromycin and oleandomycin) but remain susceptible to spiramycin. Introduction Spiramycin belongs to the group of macrolide antibiotics which contain a large lactone ring (12-16 atoms) with few double bonds and no nitrogen atoms. In addition, the ring is substituted with one or more sugar residues, some of which may be aminosugars. Closer examination of the structure of macrolides suggest that they fall into several groups, the most important of which are the erythromycin group (erythromycin and oleandomycin), the spiramycin group (tylosin, relomycin, angolamycin and others) and the carbomycin group (including niddamycin and leucomycin). Structures of erythromycin, spiramycin and carbomycin are given in Figure 1. These antibiotics, with different potency, inhibit bacterial protein synthesis Correspondence to: Dr P. Courvalin. 13 0305-7453/88/22B013 + 11 $02.00/0 © 1988 The British Society for Antimicrobial Chemotherapy 14 A. Brisson-Noel et al. Downloaded from https://academic.oup.com/jac/article/22/Supplement_B/13/714054 by guest on 02 October 2021 Erythromycin A Spiramycin R = H II R=COCH3 III R = COCH 2CH) Carbomycin A Figure 1. Chemical structures of the major macrolide antibiotics. Mode of action of spiramycin 15 both in vivo and in vitro (Vazquez, 1967). Like many other inhibitors of protein synthesis, they are generally bacteriostatic, although at very high concentrations some macrolides may be bactericidal. Spiramycin and other macrolides display selective toxicity, since they are active against bacteria but not against eukaryotes. Although it has been now clearly established that macrolides block the functions of the bacterial ribosome, the mechanism by which they accomplish this inhibition is still not clear. Downloaded from https://academic.oup.com/jac/article/22/Supplement_B/13/714054 by guest on 02 October 2021 Mechanism of protein synthesis Proteins are constituted by one or more polypeptide chains which are polymers of L-aminoacids. Before integration into polypeptides, amino acids are attached to specific transfer RNA (tRNA) by enzymes specific for each aminoacid (aminoacyl-tRNA­ synthetases). The resulting complexes are carried to the ribosome where the specificity of protein synthesis is achieved by pairing between the anticodon in the incoming aminoacyl-tRNA and the complementary codon in messenger RNA (mRNA). Protein synthesis occurs in Escherichia coli through three steps (initiation, elongation and termination) requiring different cofactors (Figure 2). Initiation step The first event of this step is the binding of the 30S subunit to the correct site on mRNA, which involves complementary base pairing between the 3' terminus of 16S rRNA and a sequence of nucleotides upstream from the initiator codon (Shine & Dalgarno, 1974). Polypeptide chain synthesis is initiated by particular tRNA specific for methionine, tRNAF , which allows formylation of the aminogroup of bound methionine. The anticodon of tRNAF recognizes the AUG or GUG initiation co dons in mRNA. Another species of tRNA, tRNAM , does not allow formylation of bound methionine and is used to insert methionine at internal positions in polypeptide chains. Specific initiation factors (IF-I, IF-2, and IF-3) and GTP direct the binding of formylmethionine-tRNAF and mRNA to the smaller ribosomal subunit to form the 'initiation complex'. Then the 50S ribosomal subunit is added to the initiation complex while GTP is hydrolysed and the initiation factors are released. Elongation step Addition of the large ribosomal subunit to the initiation complex places the fMet tRNAF in a particular site of this subunit, the peptidyl donor or P site. The aminoacyl­ tRNA bearing the next amino acid binds to an adjacent site, the aminoacyl acceptor or A site. Peptide bond formation involves transfer of the fMet-tRNA from the tRNAF bound in the P site to the aminoacyl-tRNA bound in the A site. This reaction, which does not require exogenous energy or supernatant factors, is catalysed by an enzyme, the peptidyl transferase, which is an integral part of the 50S subunit. Then the new peptidyl-tRNA (tRNA bearing the nascent peptide) shifts from the A site to the P site and the old deacylated tRNA (which previously bore the nascent peptide) is released from the P site, while the ribosome moves towards the 3' end of the mRNA by one codon shift. This reaction, designated translocation, involves the elongation factor EF-G and hydrolysis of one GTP molecule. The amino acyl-tRNA binding reaction requires the elongation factor EF-Tu and hydrolysis of one GTP molecule. -0\ • INITIATION • IF 1,IF-2 5 m'''' Q ~ f "/f ~ /// ~ ..~: /-t> IF-3 IF 1,IF-2 T T GTP z 1'.",""t ra n sfer 0 ~ ~ - reaction t- « :3.=fI) .... G fI) /( <!) Q Z :r T 0 Qz I ...J aan ~ ~ UJ ... ~an '" aa n-1 ~ + I I I \ ~a2 <] fMel <]1--- ~ \ ~a2 \ RF,GTP fMel EF-G,GTP Translocation • TERMINATION • F'igure 2. Simplified scheme of protein synthesis mechanism. Recycling of aminoacyl-tRNA and of ribosomes is not indicated. A, Aminoacyl acceptor site; aa, amino acid; EF, elongation factor; !Met, forrnylmethionine; IF, initiation factor; P, peptidyl donor site; RF, releasing factor. Downloaded from https://academic.oup.com/jac/article/22/Supplement_B/13/714054 by guest on 02 October 2021 October 02 on guest by https://academic.oup.com/jac/article/22/Supplement_B/13/714054 from Downloaded Mode of action of spiramycin 17 Downloaded from https://academic.oup.com/jac/article/22/Supplement_B/13/714054 by guest on 02 October 2021 Puromycin Figure 3. Structure of puromycin. Termination step Termination of polypeptide chains is signalled by three termination codons (UAA, UAG, and UGA) in mRNA. When a termination codon is reached, the release of the peptidyl-tRNA from the ribosome is promoted by three releasing factors (RF-l, RF-2, and RF-3). The hydrolysis of the ester linkage between the polypeptide and the tRNA is achieved by a peptidyl-tRNA hydrolase. Detachment of the deacylated-tRNA and mRNA from the ribosome is promoted by factor EF-G and another protein designated RRF (ribosome release factor). Clarification of the mechanism of protein synthesis was associated with the elucidation of the mode of action of puromycin. This antibiotic, which is a structural analogue of the 3'-terminus of aminoacyl-tRNA (Figure 3), takes part in the ribosomal peptide-bond forming reaction and accepts the nascent peptide chain. Since puromycin binds only weakly to ribosomes, the resultant peptidyl-puromycin molecule usually falls off the ribosome almost at once. Binding of spiramycin to ribosomes Spiramycin, like other macrolides, binds to 50S ribosomal subunits (Vazquez, 1967) apparently with 1: I stoichiometry (Pestka, Nakagawa & Omura, 1974). This antibiotic and various macrolides compete with each other (Fernandez-Munoz et aI., 1971) for ribosomal binding sites to which they attach with dissociation constants in the range 10 - 8 -10 - 7. This competition suggested that all macrolides may bind at overlapping or identical sites on the ribosome. From experiments based on competitive binding of antibiotics and leucyl-pentanucleotide fragment (CACCA-Leu-Ac) from leucyl-tRNA on 50S subunit, it was reported that spiramycin and carbomycin blocked the P site of peptidyl transferase and also exerted an inhibitory action on substrate­ binding at the A site (Celma, Monro & Vazquez, 1970). On the contrary, erythromycin was shown to stimulate substrate-binding at the P site. Several studies intending to identify the ribosomal proteins that bound the antibiotics gave conflicting results. Using reconstitution experiments of the 50S subunit, Teraoka & Nierhaus (1978) demonstrated that proteins LI5 and LI6 were 18 A. Brisson-Noel et al. required for both erythromycin binding and peptidyl transferase activity. Siegrist, Moreau & Le Goffic (1984) used the technique of protein labelling with photoreactive dihydrorosaramycin to show that rosaramycin could bind to proteins L 1, L5, L6 and S 1.
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