, Volume 51, Supplement 1, pp 20–30 | Cite as

Mechanism of Action of Streptogramins and Macrolides

  • Pascal Vannuffel
  • Carlo Cocito


Protein synthesis is catalysed by ribosomes and cytoplasmic factors. Bacterial ribosomes (70S) are made up of 2 subunits (50S and 30S) containing ribosomal RNA (rRNA) and ribosomal proteins: the 30S binds messenger RNA and begins the ribosomal cycle (initiation), whereas 50S binds transfer RNA (tRNA) derivatives and controls elongation. The key reaction, peptide bond formation, is promoted by the catalytic centre of 50S (the peptidyl transferase centre), and the growing peptide chain (peptidyl-tRNA) attached at the donor P site undergoes peptide linkage with an aminoacyl-tRNA at the acceptor A site. This reaction is inhibited by several antibiotics, the best known being chloramphenicol, and the macrolide-lincosamide-streptogramin (MLS) group. These inhibitors have a reversible action, except for streptogramins that are composed of A and B components, which are bacteriostatic alone, but bactericidal when combined.

The peptidyl transferase centre has been identified at the 50S surface, and the binding sites of inhibitors have been mapped within this domain: some of these sites overlap (e.g. those of macrolides, and type B streptogramins, which compete for binding to ribosomes). Chloramphenicol blocks the catalytic portion, and A streptogramins the substrate sites of the peptidyl transferase centre. Macrolides and type B streptogramins interfere with the formation of long polypeptides and cause a premature detachment of incomplete peptide chains. The synergism between types A and B streptogramins is due to induction by type A streptogramins of an increased ribosome affinity for type B streptogramins.

Microbial resistance to antibiotics mainly involves inactivation of inhibitors and modification of targets (mutations of ribosomal proteins or rRNA genes). Alterations of rRNA bases can induce resistance to a single inhibitor or to a group of antibiotics (e.g. MLSB). The impact of resistance in chemotherapy is less important for streptogramins than for other inhibitors, because the synergistic effect of A and B streptogramins also applies to strains resistant to the MLSB group. It is proposed that mutations and modifications of rRNA bases induce conformational ribosomal changes that prevent antibiotics binding to the target. Conformational changes are also triggered by type A streptogramins: they are responsible for their synergism with type B streptogramins.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cocito C. Textbook of Microbiology. Brussels: Catholic University of LouvainGoogle Scholar
  2. 2.
    Cocito C. Antibiotics of the virginiamycin family, inhibitors which contain synergistic components. Microbiol Rev 1979; 43: 145–98.PubMedGoogle Scholar
  3. 3.
    Vazques D. The streptogramin family of antibiotics. In: Corcoran JW, Hahn FE, editors. Antibiotics. Vol. 3. Heidelberg: Springer Verlag, 1975: 521–34.Google Scholar
  4. 4.
    Chinali G, Di Giambattista M, Cocito C. Ribosome protection by tRNA derivatives against inactivation by virginiamycin M. Evidence for 2 types of interaction of tRNA with the donor site of the peptidyltransferase. Biochemistry 1987; 26: 1592–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Di Giambattista M, Thielen A, Maassen J, et al. Localisation of virginiamycin S binding site on bacterial ribosome by fluorescence energy transfer. Biochemistry 1986; 25: 3540–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Di Giambattista M, Nyssen E, Pecher A, et al. Affinity labeling of the virginiamycin S binding site on bacterial ribosome. Biochemistry 1990; 29: 9203–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Cocito C. Properties of virginiamycin-like antibiotics (synergimycins), inhibitors containing synergistic components. In: Corcoran JW, Hahn FE, editors. Antibiotics. Berlin: Springer Verlag 1983; V1: 296–332Google Scholar
  8. 8.
    Chinali G, Vanlinden F, Cocito C. Action of virginiamycin M on the stability of different ribosomal complexes to ultracentrifugation. Biochim Biophys Acta 1988; 950: 67–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Lai CJ, Weisblum B. Altered methylation of ribosomal RNA in an erythromycin-resistant strain of Staphylococcus aureus? Proc Natl Acad Sci USA 1971; 68 (4): 856–60.PubMedCrossRefGoogle Scholar
  10. 10.
    Moazed D, Noller HF. Chloramphenicol, erythromycin, carbomycin and vernamycin B protect overlapping sites in the peptidyl transferase region of 23S rRNA. Biochemie 1987; 69: 879–84.CrossRefGoogle Scholar
  11. 11.
    Noller HF. Ribosomal RNA and translation. Ann Rev Biochem 1991; 60: 191–227.PubMedCrossRefGoogle Scholar
  12. 12.
    Vannuffel P, Di Giambattista M, Morgan EA, et al. Identification of a single base change in ribosomal RNA leading to erythromycin resistance. J Biol Chem 1992; 267: 8377–82.PubMedGoogle Scholar
  13. 13.
    Vannuffel P, Di Giambattista M, Cocito C. The role of rRNA bases in the interaction of peptidyltransferase inhibitors with bacterial ribosomes. J Biol Chem 1992; 267: 16114–20.PubMedGoogle Scholar
  14. 14.
    Cundliffe E. On the nature of antibiotic binding sites in ribosomes. Biochimie 1987: 69: 863–9PubMedCrossRefGoogle Scholar
  15. 15.
    Di Giambattista M, Chinali G, Cocito C. The molecular basis of the synergistic inhibitor activity of type A and B synergimycins on ribosomes. J Antimicrob Chemother 1989; 24: 485–507.PubMedCrossRefGoogle Scholar
  16. 16.
    Parfait R, Cocito C. Lasting damage to bacterial ribosomes by reversibility-bound virginiamycin M. Proc Natl Acad Sci USA 1980 77: 5492–6PubMedCrossRefGoogle Scholar
  17. 17.
    Nyssen E, Di Giambattista M, Cocito C. Analysis of the reversible binding of virginiamycin M to ribosome and particle functions after removal of the antibiotic. Biochim Biophy Acta 1989; 1009: 39–46.CrossRefGoogle Scholar
  18. 18.
    Di Giambattista M, Nyssen E, Engelborghs Y, et al. Kinetics of binding of macrolides, lincosamides and synergimycins to ribosomes. J Biol Chem 1987; 262: 8591–7.PubMedGoogle Scholar
  19. 19.
    Cocito C, Chinali G. Molecular mechanisms of virginiamycin-like antibiotics on bacterial cell-free systems for protein synthesis. J Antimicrob Chemother 1985; 16 Suppl. A: 35–52.PubMedGoogle Scholar
  20. 20.
    Chinali G, Moureau Ph, Cocito C. The action of virginiamycin M on the acceptor, donor and catalytic sites of peptidyltransferase. J Biol Chem 1984; 259: 9563–9.PubMedGoogle Scholar
  21. 21.
    Chinali G, Nyssen E, Di Giambattista M, et al. Inhibition of polypeptide synthesis in cell-free systems by virginiamycin S and erythromycin. Evidence for a common mode of action of type B synergimycins and 14-membered macrolides. Biochim Biophys Acta 1988; 949: 71–8.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Pascal Vannuffel
    • 1
  • Carlo Cocito
    • 1
  1. 1.Department of Genetics and MicrobiologyCatholic University of LouvainBruxellesBelgium

Personalised recommendations