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Contributed by Ada Yonath, September 17, 2015 (sent for review August 19, 2015)
Significance
Clinical use of the currently available antibiotics is severely compromised by the increasing resistance to them, acquired by the natural bacterial capability to manipulate their genomes. Many existing antibiotics target the fundamental process of protein biosynthesis, mainly by paralyzing the ribosome. Although antibiotics’ modes of action are similar across most eubacteria, species specificity has been detected. We determined the structures of the large ribosomal subunit from Staphylococcus aureus, a pathogenic bacterial species with a known capacity to become multiresistant, and of its complexes with known antibiotic compounds, as well as with a novel potential pleuromutilin derivative. Our new insights provide unique chemical tools for enhanced distinction between pathogens and the useful benign microbiome, as well as for suggesting novel sites for potential future antibiotics.
Abstract
The emergence of bacterial multidrug resistance to antibiotics threatens to cause regression to the preantibiotic era. Here we present the crystal structure of the large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with the known antibiotics linezolid and telithromycin, as well as with a new, highly potent pleuromutilin derivative, BC-3205. These crystal structures shed light on specific structural motifs of the S. aureus ribosome and the binding modes of the aforementioned antibiotics. Moreover, by analyzing the ribosome structure and comparing it with those of nonpathogenic bacterial models, we identified some unique internal and peripheral structural motifs that may be potential candidates for improving known antibiotics and for use in the design of selective antibiotic drugs against S. aureus.
Footnotes
↵1Z.E. and D.M. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: ada.yonath{at}weizmann.ac.il.
Author contributions: A.B. and A.Y. designed research; Z.E., D.M., M.K., I.W., E.Z., H.R., and A.B. performed research; S.P. contributed new reagents/analytic tools; Z.E., D.M., M.K., I.W., E.Z., H.R., and A.B. analyzed data; and Z.E., D.M., A.B., and A.Y. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 4WCE, 4WFB, 4WF9, and 4WFA).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1517952112/-/DCSupplemental.
Freely available online through the PNAS open access option.
Species specificity of a ribosome from a pathogen
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