| Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent. | |
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MedLine Citation:
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PMID: 20833054 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A class of cyclic acyldepsipeptide antibiotics collectively known as the enopeptins has recently attracted much attention because of their activity against multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. These antibiotics are further distinguished by their novel mechanism of action in which they bind and deregulate the tightly controlled activity of the cytoplasmic protease ClpP. Although the natural products have poor pharmacological properties, a synthetic derivative called acyldepsipeptide 4 (ADEP 4) showed remarkable antibacterial activity both in vitro and in mouse models of bacterial infections. A novel route to the ADEP 4 peptidolactone core structure, featuring the Joullié-Ugi three-component reaction, was developed. This multicomponent reaction and a related multicomponent reaction, the Ugi four-component reaction, were used to prepare analogs that were designed using the principles of conformational analysis. These cyclic acyldepsipeptides were tested for their activity against drug-resistant, clinical isolates of Staphylococci and Enterococci. One ADEP 4 analog in which the pipecolate was replaced by 4-methyl pipecolate exhibited in vitro antibacterial activity against Enterococci that was fourfold higher than the parent compound. |
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Authors:
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Aaron M Socha; Nicholas Y Tan; Kerry L LaPlante; Jason K Sello |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-19 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: 18 ISSN: 1464-3391 ISO Abbreviation: Bioorg. Med. Chem. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-04 Completed Date: 2011-01-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: England |
Other Details:
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Languages: eng Pagination: 7193-202 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Chemistry, Brown University, Providence, RI 02912, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Bacterial Agents / chemical synthesis*, chemistry, therapeutic use Bacterial Infections / drug therapy Bacterial Proteins / antagonists & inhibitors, metabolism Depsipeptides / chemical synthesis, chemistry*, therapeutic use Drug Evaluation, Preclinical Drug Resistance, Bacterial / drug effects Enterococcus / drug effects Methicillin-Resistant Staphylococcus aureus / drug effects Mice Microbial Sensitivity Tests |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Bacterial Proteins; 0/Depsipeptides |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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