Total synthesis of lysobactin.

Abstract

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 microg/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.

• Authors: Aikomari Guzman-Martinez, Ryan Lamer, Michael S VanNieuwenhze
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 129 Issue 18 Pg. 6017-21 (May 09 2007) ISSN: 0002-7863 [Print] United States
• PMID: 17432854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Depsipeptides
• katanosin B

Topics

• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Cyclization
• Depsipeptides (chemical synthesis, chemistry, pharmacology)
• Methicillin Resistance
• Microbial Sensitivity Tests
• Molecular Structure
• Staphylococcus aureus (drug effects)