Redesign of glycopeptide antibiotics: back to the future

Abstract

The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistant bacterial infections including those caused by methicillin-resistant Staphylococcus aureus (MRSA). After more than 50 years of clinical use, the emergence of glycopeptide-resistant Gram-positive pathogens such as vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) presents a serious global challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments including the development of new derivatives of the glycopeptide antibiotics. General approaches have been explored for modifying glycopeptide antibiotics, typically through the derivatization of the natural products themselves or more recently through chemical total synthesis. In this Perspective, we consider recent efforts to redesign glycopeptide antibiotics for the treatment of resistant microbial infections, including VRE and VRSA, and examine their future potential for providing an even more powerful class of antibiotics that are even less prone to bacterial resistance.

Figure 1

Late stage bacterial cell wall synthesis and vancomycin binding to D-Ala-D-Ala.

Figure 2

Structures of oritavancin, telavancin, and teicoplanin.

Figure 3

Schematic representation of the interaction of vancomycin with model ligands and measured binding data.

Figure 4

Key vancomycin residue 4 modifications.

Scheme 1

Summary of synthetic strategy.

Scheme 2

Single-step synthetic conversion of a residue 4 thioamide to the corresponding amidine and its dual binding behavior toward D-Ala- D-Lac and D-Ala- D-Ala.