Journal Article

Ribosome clearance by FusB-type proteins mediates resistance to the antibiotic fusidic acid

Savelsbergh, Andreas, Rodnina, Marina V, Thompson, Gary S, Homans, Steve W, Edwards, Thomas A, Jenkins, Huw T, Cox, Georgina, O'Neill, Alexander J, Peske, Frank, Wintermeyer, Wolfgang

2012

Overview

Resistance to the antibiotic fusidic acid (FA) in the human pathogen Staphylococcus aureus usually results from expression of FusB-type proteins (FusB or FusC). These proteins bind to elongation factor G (EF-G), the target of FA, and rescue translation from FA-mediated inhibition by an unknown mechanism. Here we show that the FusB family are two-domain metalloproteins, the C-terminal domain of which contains a four-cysteine zinc finger with a unique structural fold. This domain mediates a high-affinity interaction with the C-terminal domains of EF-G. By binding to EF-G on the ribosome, FusB-type proteins promote the dissociation of stalled ribosome⋅EF-G⋅GDP complexes that form in the presence of FA, thereby allowing the ribosomes to resume translation. Ribosome clearance by these proteins represents a highly unusual antibiotic resistance mechanism, which appears to be fine-tuned by the relative abundance of FusB-type protein, ribosomes, and EF-G.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Anti-Bacterial Agents - pharmacology / Antibiotic resistance / Antibiotics / Bacterial Proteins - metabolism / Binding Sites / Biochemistry / Biological Sciences / Cadmium / Chemical equilibrium / Crystal structure / Crystallography, X-Ray / dissociation / Drug Resistance, Bacterial - drug effects / Elongation / Fusidic acid / Fusidic Acid - pharmacology / Humans / metalloproteins / Models, Biological / Models, Molecular / Pathogens / Peptide Elongation Factor G - metabolism / Peptide elongation factors / Protein Binding - drug effects / Protein Interaction Maps / Proteins / Relative abundance / Resistance mechanisms / Ribosomes / Ribosomes - drug effects / Ribosomes - metabolism / Staphylococcus aureus / Staphylococcus infections / Translation / Zinc / zinc finger motif / Zinc finger proteins