Total synthesis of lysobactin.
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.
Guzman-Martinez
Aikomari
A
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA.
Lamer
Ryan
R
VanNieuwenhze
Michael S
MS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; C056790:katanosin B