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The bacterial ribosome as a target for antibiotics

Key Points

  • A large proportion of clinically useful antibiotics exert their antimicrobial effects by blocking protein synthesis on the ribosome. The bacterial ribosome is a ribonucleoprotein complex of about 2.5 million Daltons, and is composed of two subunits that are named after their sedimentation values of 30S and 50S.

  • The molecular details of the ribosome have recently been determined by X-ray crystallography. Different organisms have been used as the source of ribosomal particles for crystallization.

  • Well resolved structures have been obtained for the 30S subunit and the intact ribosome from the bacterium Thermus thermophilus. The best resolved structures for the 50S subunit come from the bacterium Deinococcus radiodurans and the archaeon Haloarcula marismortui.

  • These crystal structures reveal the molecular details of the antibiotic-binding sites. Furthermore, they explain many earlier observations from biochemical and genetic studies including: how drugs exercise their inhibitory effects; how some drugs in combination enhance or impede each other's binding; and how alterations to ribosomal components confer resistance.

  • The antibiotic-binding sites are located within functionally important structures in the ribosomal RNA (rRNA). Antibiotic resistance is often conferred by base substitution or methylation at these sites in the rRNA. However, resistance can also be conferred by mutations in ribosomal proteins that influence these rRNA structures.

  • Resistance can be counteracted by equipping current antibiotics with new chemical substituents that improve their binding. Perhaps even greater potential, which is presently unrealized, lies in the rational design of novel compounds that target unexploited sites within the ribosome structure.

Abstract

Many clinically useful antibiotics exert their antimicrobial effects by blocking protein synthesis on the bacterial ribosome. The structure of the ribosome has recently been determined by X-ray crystallography, revealing the molecular details of the antibiotic-binding sites. The crystal data explain many earlier biochemical and genetic observations, including how drugs exercise their inhibitory effects, how some drugs in combination enhance or impede each other's binding, and how alterations to ribosomal components confer resistance. The crystal structures also provide insight as to how existing drugs might be derivatized (or novel drugs created) to improve binding and circumvent resistance.

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Figure 1: Binding sites of antibiotics on the bacterial ribosome.
Figure 2: Chemical structures of a selection of ribosome-targeting drugs.
Figure 3: The decoding site at the interface of the 30S ribosomal subunit.
Figure 4: Binding sites of macrolide, lincosamide, streptogramin B (MLSB) antibiotics within the 50S subunit tunnel.

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Acknowledgements

Support from the Danish Research Agency and the Nucleic Acid Center of the Danish Grundforskningsfond are gratefully acknowledged.

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Correspondence to Stephen Douthwaite.

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DATABASES

Entrez

Deinococcus radiodurans

Escherichia coli

Haloarcula marismortui

Thermus thermophilus

FURTHER INFORMATION

Stephen Douthwaite's laboratory

The Protein Data Bank

Glossary

HAIRPIN

A structural element that makes a 180° turn and doubles back on itself; in proteins, normally formed from a β-strand.

POLYKETIDES

Secondary metabolites that are biosynthesized in a stepwise manner from simple 2-, 3- and 4-carbon building blocks; can have antimicrobial, antifungal, antiparasitic, antitumour or agrochemical properties.

MACROLACTONE RING

The cyclic ester ring at the core of macrolide antibiotics.

MACROLIDE 5-AMINO SUGAR

The nitrogen-containing sugar directly attached to the 5-carbon of the macrolactone ring (desosamine in erythromycin and mycaminose in tylosin).

ELECTROSTATIC INTERACTIONS

Interactions between charged molecules or atoms.

HYDROPHOBIC INTERACTIONS

Interactions that rely on the tendency of non-polar groups to aggregate to avoid contact with a polar solvent.

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Poehlsgaard, J., Douthwaite, S. The bacterial ribosome as a target for antibiotics. Nat Rev Microbiol 3, 870–881 (2005). https://doi.org/10.1038/nrmicro1265

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