Total synthesis of lysobactin : a natural product antibiotic active against methicillin and vancomycin resistant bacteria

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 is a cyclic depsipeptide antibiotic produced by a species of Lysobacter (ATCC53042) that was isolated by a group at the Squibb Institute. In a recent evaluation, lysobactin 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 [mu]g/mL.12 The MIC values against VRE were more than 50- fold lower than those reported for vancomycin itself. Lysobactin inhibited the incorporation of isotopically labeled N-acetylglucosamine (GlcNAc) into staphylococcal cell wall peptidoglycan with a 50% inhibitory concentration (IC₅₀) 0.78 [mu]g/mL very close to its MIC. Lysobactin was also found to inhibit nascent peptidoglycan formation; however, unlike vancomycin, its activity was not antagonized in the presence of N-acetyl-L-Lys-D-Ala-D- Ala. Thus, if lysobactin achieves its inhibition of the peptidoglycan biosynthetic machinery through binding to the lipid intermediates or nascent peptidoglycan, it does so at a site on these precursors that is not utilized by vancomycin itself. 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 analogue