STRUCTURAL BASIS FOR LINEZOLID BINDING SITE REARRANGEMENT IN THE STAPHYLOCOCCUS AUREUS RIBOSOME
The ribosome, an assembly of RNA and proteins, translates the genetic code into proteins in all living cells. As the ribosomes are essential for cell life, inhibiting their function will damage the cell. As a result, about 40% of the antibiotics, which are in clinical use, target functional centers in the ribosome. The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent pathogen Staphylococcus aureus resistance to last line antimicrobial drugs such as linezolid.
Here we present single-particle reconstruction cryo-electron microscopy studies on the structures of the 70S ribosomes from a wild type Staphylococcus aureus vs. a clinical isolate . An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed. This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site. This work may provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance
Also, new features of the Staphylococcus aureus large ribosomal subunit, which were missing in the crystal structure , were revealed.