Abstract
The increasing appearance of pathogenic bacteria with antibiotic resistance is a global threat. Consequently, clinically available potent antibiotics that are active against multidrug resistant pathogens are becoming exceedingly scarce. Ribosomes are a main target for antibiotics, and hence are an objective for novel drug development. Lefamulin, a semi-synthetic pleuromutilin compound highly active against multi-resistant pathogens, is a promising antibiotic currently in phase III trials for the treatment of community-acquired bacterial pneumonia in adults. The crystal structure of the Staphylococcus aureus large ribosomal subunit in complex with lefamulin reveals its protein synthesis inhibition mechanism and the rationale for its potency. In addition, analysis of the bacterial and eukaryotes ribosome structures around the pleuromutilin binding pocket has elucidated the key for the drug's selectivity.
| Original language | English |
|---|---|
| Article number | 39004 |
| Journal | Scientific Reports |
| Volume | 6 |
| DOIs | |
| Publication status | Published - 13 Dec 2016 |
Funding
European Research Council [322581]; Kimmelman Center for Macromolecular Assemblies; Adams Fellowship; Martin S. and Helen Kimmel Professorial Chair at the Weizmann Institute of Science We thank Dr. Moshe Peretz, Shoshana Tel- Or, Miriam Lachever and Maggie Kessler for their interest and experimental support; Astrid Gruss for S. aureus ribosome preparation; staff members at Beamlines ID23-1 of the European Synchrotron Radiation Facility/European Molecular Biology Laboratory for their assistance during data collection. Funding was provided by European Research Council Grants 322581 (NOVRIB) and the Kimmelman Center for Macromolecular Assemblies. M.K. is a recipient of an Adams Fellowship. A.Y. holds the Martin S. and Helen Kimmel Professorial Chair at the Weizmann Institute of Science.
All Science Journal Classification (ASJC) codes
- General