Max Planck Institute for Molecular Genetics

	Group leader: Francois Franceschi

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50S-antibiotic complexes

We determined the structure of the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans complexed with the clinically relevant antibiotics chloramphenicol, clindamycin, and the three macrolides: erythromycin, clarithromycin, and roxithromycin.

The antibiotic chloramphenicol, a product isolated originally from Streptomyces venezuelae, is effective in the treatment of a wide variety of bacterial infections, including serious anaerobic infections, but is rarely used in Western countries because of concerns about toxicity. Nevertheless, it has become the classical inhibitor of the peptidyl transferase reaction for biochemists.

The lincosamide antibiotic clindamycin is a semi-synthetic derivate from lincomycin. It is effective in the treatment of most infections involving anaerobes and gram-positive cocci.

Erythromycin is a macrolide antibiotic produced by Streptomyces erythreus.The erythromycin class of macrolides has few side effects for humans, and is effective against a wide variety of bacterial infections.

The antibiotic binding sites for the five antibiotics are composed exclusively of segments of 23S ribosomal RNA at the peptidyl transferase cavity and do not involve any interaction of the drugs with ribosomal proteins. In addition, putative Mg +2 ions may be important for the binding of chloramphenicol. Our structural analysis should facilitate rational drug design.

3D-diagram

2D-diagram

50S-chloramphenicol interactions

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50S-clindamycin interactions

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50S-macrolide interactions

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Chloramphenicol mainly targets the A site of the 50S subunit, where it interferes directly with substrate binding. Clindamycin, on the other hand, interferes with substrate binding at the A site and the P site and physically hinders the path of the growing peptide chain. Macrolides bind at the entrance to the tunnel where they sterically block the progression of the nascent peptide.

Top view of the 50S ribosomal subunit from D. radiodurans showing erythromycin (red) bound to the entrance of the tunnel. Blue, 23S rRNA and 5S rRNA. Gold, ribosomal proteins.

Although the binding sites of the antibiotics differ from each other, they show some overlapping nucleotides. The structural model of the peptidyl transferase center in complex with the examined antibiotics should not only enable a rational approach for antibiotic development and therapy strategies but could be also used to identify new target sites on the eubacterial ribosome.

You can read more on the subject in the original article:

Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Schlünzen F., Zarivach R., Harms J.,Bashan A., Tocilj A., Albrecht R., Yonath A.& Franceschi F. Nature 413, 814-821 (2001).

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