Document Detail


Beta-lactones as specific inhibitors of ClpP attenuate the production of extracellular virulence factors of Staphylococcus aureus.
MedLine Citation:
PMID:  18847196     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To approach the daunting problem of multidrug resistant bacterial pathogens, a multidisciplinary chemical proteomic strategy was applied and functionalized beta-lactones were identified as potent, cell permeable inhibitors for specific and selective targeting of the key virulence regulator complex ClpP in S. aureus and methicillin resistant S. aureus (MRSA) strains. ClpP represents the central protease complex responsible for the activation of numerous virulence factors including many with devastating effects for human health such as hemolysins, proteases, lipases, and DNases. Although the crucial role of this enzyme was validated by genetic knockouts, no inhibitor has been reported to date. In fact, our most potent inhibitor was able to completely abolish hemolytic and proteolytic activities and showed a dramatic decrease in the activities of virulence associated lipases and DNases. These effects were also observed in a multiresistant strain emphasizing the potential value of such compounds. Targeting this virulence factor may therefore likely represent an attractive strategy for neutralizing the harmful effects of bacterial pathogens and help the host immune response to eliminate the disarmed bacteria. Since ClpP is not essential for viability and highly conserved in many pathogens, our strategy could represent a global approach for the treatment of infectious diseases without the pressing problem of antibiotic pressure and resistance development.
Authors:
Thomas Böttcher; Stephan A Sieber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-11
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  130     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-10-30     Completed Date:  2008-12-24     Revised Date:  2009-01-27    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14400-1     Citation Subset:  IM    
Affiliation:
Center for integrated Protein Science Munich CIPS(M), Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Endopeptidase Clp / antagonists & inhibitors*,  metabolism
Lactones / chemistry,  pharmacology*
Methicillin-Resistant Staphylococcus aureus / drug effects,  enzymology,  metabolism
Serine Proteinase Inhibitors / chemistry,  pharmacology*
Staphylococcus aureus / drug effects,  enzymology*,  metabolism
Substrate Specificity
Virulence Factors / antagonists & inhibitors*,  biosynthesis
Chemical
Reg. No./Substance:
0/Lactones; 0/Serine Proteinase Inhibitors; 0/Virulence Factors; EC 3.4.21.92/Endopeptidase Clp

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