Chapter 14. Semisynthetic Glycopeptide Antibiotics

Abstract

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.