Antibiotics targeting the ribosome

Antibiotics Targeting the Ribosome Structure-Based Design and the Nobel Prize... 

Macrolide antibiotics target the bacterial ribosome and inhibit the bacterial protein biosynthesis. Many gram-negative bacteria are inherently resistant to mac-rolides because their outer membrane is impermeable to macrolides. Several mechanisms of acquired resistance have been reported. In some cases, resistance is conferred by methylation of ribosomes by methylase enzymes, the genes of... 

Sutcliffe JA Improving on nature antibiotics that target the ribosome. Curr Opin Microbiol. 2005 8 534-542. 

Rational efforts to design new antibiotics that target the ribosome became feasible when the crystal structures of both ribosomal subunits were solved at atomic resolution in 2000 [1-3]. Since then, structures of about 20 different antibiotics bound to ribosomes have been published (Tab. 4.1) [4—12]. These structures of antibiotic/ribosomal complexes provide insights into the mechanisms by which antibiotics inhibit protein synthesis and by which mutations confer resistance. Thus, a sound basis now exists for designing new antibiotics that may circumvent resistance. 

Sutcliffe, J.A. Improving on nature Antibiotics that target the ribosome. Curr. Opin. Microbiol. 

Macrolides are a group of antibiotics, produced in nature by many actinomycetes strains, that are composed of a 12- to 16-membered lactone ring, to which one or more sugar substituents is attached. They target the peptidyl transferase center on the 50S ribosomal subunit and function primarily by interfering with movement of the nascent peptide away from the active site and into the exit tunnel. 

The ribosome is the cellular target of a large and chemically diverse group of antibiotics. The antibiotic binding sites are clustered at functional centers of the ribosome and the majority are composed exclusively of RNA. The drugs interfere with the positioning and movement of substrates, products and ribosomal components that are essential for protein synthesis. 

Plasmid- ortransposon-encoded chloramphenicol acetyltransferases (CATs) are responsible for resistance by inactivating the antibiotic. CATs convert chloramphenicol to an acetoxy derivative which fails to bind to the ribosomal target. Several CATs have been characterized and found to differ in properties such as elecfrophorefic mobilify and cafalyfic acfivify. 

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