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.
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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Support from the Danish Research Agency and the Nucleic Acid Center of the Danish Grundforskningsfond are gratefully acknowledged.
The authors declare no competing financial interests.
A structural element that makes a 180° turn and doubles back on itself; in proteins, normally formed from a β-strand.
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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