Ribosome clearance by FusB-type proteins mediates resistance to the antibiotic fusidic acid.
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.
Institute of Molecular and Cellular Biology,  University of Leeds, Leeds LS2 9JT,  United Kingdom.
Georgina
G
Cox
Gary S
GS
Thompson
Huw T
HT
Jenkins
Frank
F
Peske
Andreas
A
Savelsbergh
Marina V
MV
Rodnina
Wolfgang
W
Wintermeyer
Steve W
SW
Homans
Thomas A
TA
Edwards
Alexander J
AJ
O'Neill
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005672:Fusidic Acid / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D020653:Peptide Elongation Factor G / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C492443:FusB protein, Staphylococcus aureus; D020653:Peptide Elongation Factor G; D005672:Fusidic Acid