Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
Matthew J. Belousoff,
Zohar Eyal,
Mazdak Radjainia,
Tofayel Ahmed,
Rebecca S. Bamert,
Donna Matzov,
Anat Bashan,
Ella Zimmerman,
Satabdi Mishra,
David Cameron,
Hans Elmlund,
Anton Y. Peleg,
Shashi Bhushan,
Trevor Lithgow,
Ada Yonath
Affiliations
Matthew J. Belousoff
Infection & Immunity Program, Biomedicine Discovery Institute & Department of Microbiology, Monash University, Clayton, Australia
Zohar Eyal
Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
Mazdak Radjainia
The Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Department of Biochemistry and Molecular Biology, Monash University, Victoria, Melbourne, Australia
Tofayel Ahmed
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
Rebecca S. Bamert
Infection & Immunity Program, Biomedicine Discovery Institute & Department of Microbiology, Monash University, Clayton, Australia
Donna Matzov
Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
Anat Bashan
Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
Ella Zimmerman
Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
Satabdi Mishra
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
David Cameron
Infection & Immunity Program, Biomedicine Discovery Institute & Department of Microbiology, Monash University, Clayton, Australia
Hans Elmlund
The Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Department of Biochemistry and Molecular Biology, Monash University, Victoria, Melbourne, Australia
Anton Y. Peleg
Infection & Immunity Program, Biomedicine Discovery Institute & Department of Microbiology, Monash University, Clayton, Australia
Shashi Bhushan
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
Trevor Lithgow
Infection & Immunity Program, Biomedicine Discovery Institute & Department of Microbiology, Monash University, Clayton, Australia
Ada Yonath
Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
ABSTRACT An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus. 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. IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821–832, 2015, https://doi.org/10.1038/nrd4675 ). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance.
