Total Synthesis of Lysobactin

Aikomari Guzman-Martinez, Ryan Lamer, and Michael S. VanNieuwenhze*
Contribution from the Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093
J. Am. Chem. Soc., 2007, 129 (18), pp 6017–6021
DOI: 10.1021/ja067648h
Publication Date (Web): April 14, 2007
Copyright © 2007 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, msv@ucsd.edu

Abstract

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Antibiotic resistance has become a significant public health concern. Antibiotics that belong to new structural classes and manifest their biological activity via novel mechanisms are urgently needed. Lysobactin, a depsipeptide antibiotic has displayed very strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as vancomycin-resistant enterococci (VRE) with minimum inhibitory concentrations (MICs) ranging from 0.39 to 0.78 μg/mL. The MIC values against VRE were more than 50-fold lower than those reported for vancomycin itself. Lysobactin was found to inhibit nascent peptidoglycan formation; however, this activity was not antagonized in the presence of N-acyl-l-Lys-d-Ala-d-Ala, the binding domain on the cell wall precursors that is utilized by vancomycin. Thus, lysobactin represents a promising agent for the treatment bacterial infections due to resistant pathogens. We describe a convergent synthesis of lysobactin that relies upon a highly efficient macrocyclization reaction to assemble the 28-membered cyclic depsipeptide. This synthesis provides the foundation for further study of the mode of action utilized by lysobactin and its analogues.

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History

  • Published In Issue May 09, 2007
  • Received October 25, 2006

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