| The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics. | |
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MedLine Citation:
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PMID: 20080686 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei binds at the peptidyl transferase center of the eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, a second antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. These two antibiotics can bind to the ribosome simultaneously and display synergy in inhibiting bacterial growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery. |
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Authors:
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Tamar Auerbach; Inbal Mermershtain; Chen Davidovich; Anat Bashan; Matthew Belousoff; Itai Wekselman; Ella Zimmerman; Liqun Xiong; Dorota Klepacki; Kenji Arakawa; Haruyasu Kinashi; Alexander S Mankin; Ada Yonath |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-01-11 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-02-05 Completed Date: 2010-03-05 Revised Date: 2010-09-27 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 1983-8 Citation Subset: IM |
Affiliation:
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Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Bacterial Agents
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chemistry*,
metabolism* Binding Sites Crystallography, X-Ray Deinococcus / chemistry, metabolism Drug Discovery Drug Synergism Erythromycin / analogs & derivatives, chemistry, metabolism Macrolides / chemistry*, metabolism* Models, Molecular Molecular Structure Ribosome Subunits, Large, Bacterial / chemistry, metabolism Ribosomes / chemistry*, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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GM34360/GM/NIGMS NIH HHS; U19 AI56575/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Macrolides; 114-07-8/Erythromycin; 23623-31-6/lankacidins; 30042-37-6/kujimycin B |
| Comments/Corrections | |
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