Antibiotics targeting ribosomes: Crystallographic studies

Tamar Auerbach, Anat Bashan, Joerg Harms, Frank Schluenzen, Raz Zarivach, Heike Bartels, Ilana Agmon, Maggie Kessler, Marta Pioletti, Frano̧is Franceschi, Ada Yonath

Research output: Contribution to journalReview articlepeer-review

44 Scopus citations

Abstract

Resistance to antibiotics is a major problem in modern therapeutics. Ribosomes, the cellular organelle catalyzing the translation of the genetic code into proteins, are targets for several clinically relevant antibiotics. The ribosomes from eubacteria are excellent pathogen models. High resolution structures of the large and small ribosomal subunits were used as references that allowed unambiguous localization of almost a dozen antibiotic drugs, most of which are clinically relevant. Analyses of these structures showed a great diversity in the antibiotics' modes of action, such as interference with substrate binding, hindrance of the mobility required for the biosynthetic process and the blockage of tunnel which provides the path of exit for nascent proteins. All antibiotics studied by us were found to bind primarily to ribosomal RNA and, except for one allosteric effect, their binding did not cause major conformational changes. Antibiotics of the small ribosomal subunit may hinder tRNA binding, decoding, translocation, and the initiation of the entire biosynthetic process. The large subunit agents may target the GTPase center, interfere with peptide bond formation, or block the entrance of the nascent protein exit tunnel. The overall structure of the peptidyl transferase center and the modes of action of the antibiotic agents indicate that the ribosome serves as a template for proper positioning of tRNAs, rather than participating actively in the catalytic events associated with the creation of peptide bonds.

Original languageEnglish
Pages (from-to)169-186
Number of pages18
JournalCurrent Drug Targets - Infectious Disorders
Volume2
Issue number2
DOIs
StatePublished - 27 Jun 2002
Externally publishedYes

Keywords

  • Antibiotics
  • Chloramphenicol
  • Clindamycin
  • Edeine
  • Macrolides
  • Ribosomes
  • Tetracyline

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