The bacterial ribosome as a target for antibiotics

Abstract

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.