Richard Craig Thompson

Glycopeptide antibiotic derivatives

The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity aginst a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.

Hexapeptide Derivatives of Glycopeptide Antibiotics: Tools for Mechanism of Action Studies

ABSTRACT Hexapeptide (des-N-methylleucyl) derivatives of LY264826 were prepared in order to examine further the role of N-substituted hydrophobic side chains in defining the mechanisms of action of semisynthetic glycopeptide antibiotics. The hexapeptide of LY264826 binds to the cell wall intermediate analog l-Lys-d-Ala-d-Ala with a 100-fold lower affinity than LY264826 and inhibits Micrococcus luteus almost 200-fold more poorly than LY264826 does. Alkylation of the 4-epi-vancosamine moiety of the disaccharide significantly enhanced the antibacterial activity of the hexapeptide. Alkylation did not affect the binding affinity for d-alanyl-d-alanine residues; however, it did enhance dimerization 7,000-fold and enhanced binding to bacterial membrane vesicles noticeably compared with the levels of dimerization and binding for the unsubstituted hexapeptide. The findings from this study complement those presented in an earlier report (N. E. Allen, D. L. LeTourneau, and J. N. Hobbs, Jr., J. Antibiot. 50:677-684, 1997) and are consistent with the conclusion that the enhanced antibacterial activities of semisynthetic glycopeptide antibiotics derive from the ability of the hydrophobic side chain to markedly affect both dimerization and binding to bacterial membranes.

Chapter 14. Semisynthetic Glycopeptide Antibiotics

Publisher Summary In recent times, interest in the glycopeptide class of antibiotics has increased. A new development has been the interest in semisynthetic glycopeptides as the activity of this class can be expanded to include vancomycin resistant enterococci and even some gram-negative bacteria. The anti-bacterial effect exhibited by the glycopeptide class of antibiotics is attributed to their ability to inhibit the biosynthesis of peptidoglycan, a key structural component of the bacterial cell wall. Vancomycin and other glycopeptides antibiotics form complexes with the C-terminal D-Ala-D-Ala sequence of the bacterial cell wall precursor, thus preventing the subsequent transglycosylation and transpeptidation reactions necessary for the construction of the peptidoglycan. In addition to an affinity for D-Ala-D-Ala, other factors may also play an important role in the activity exerted by the glycopeptide antibiotics. The molecular basis of resistance to glycopeptide antibiotics is well understood. The bacteria have acquired the necessary enzymes to synthesize an altered cell wall precursor, terminating in D-lactate rather than D-alanine. The replacement of an amide linkage with an ester linkage results in the loss of one hydrogen-bond interaction between vancomycin and the ligand. Some of the most interesting semisynthetic molecules that have been reported are intrinsically complex to make and cost may limit the attractiveness of development. Nonetheless, the class provides an instructive example of the effectiveness of the union of natural product research and medicinal chemistry applied to new medical needs.