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.

Peripheral modifications of [Ψ[CH 2 NH]Tpg 4 ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

“…The results of the examination of the analogs that incorporate the two peripheral modifications (14)(15)(16)(17) and their combination with the pocket-modified vancomycin analog in 18 were even more revealing. In addition to showing that this may be successfully achieved, they highlight that it is not necessarily the most effective individual variants of the two peripheral modifications that combine to produce the desired effects but rather, that it is a combination that allows expression of the two independent mechanisms.…”

“…In recent disclosures, we have discussed attributes of the glycopeptide antibiotics (12,13) that have contributed to their sustained effectiveness in the clinic (14). Vancomycin (15), teicoplanin (16), and three recently approved semisynthetic derivatives, oritavancin (17), dalbavancin (18), and telavancin (19), are widely used to treat refractory bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) (20).…”

Targeting Antibiotic Resistance

“…The Boger group at Scripps has carried out a tremendous amount of work on the synthesis of vancomycin and its analogues, focusing on binding to d ‐Ala‐ d ‐Lac strands 131. In resistant bacteria, peptidoglycans with the d ‐Ala‐ d ‐Lac terminus only make four hydrogen bonds with vancomycin, resulting in a 1000‐fold loss in binding affinity.…”

“…This figure can be divided into two factors: a 10‐fold decrease as a result of the loss of a hydrogen bond, and a 100‐fold decrease owing to repulsion of the lone pairs on the two nearby oxygen atoms 132. In order to try and regain the lost binding affinity, a series of vancomycin analogues was synthesized with modifications at the carbonyl group of residue 4 (Figure 27 A) 131, 133…”

Synthesis and antibacterial evaluation of some teicoplanin pseudoaglycon derivatives containing alkyl- and arylthiosubstituted maleimides

“…2 The emergence and spread of glycopeptide-resistant enterococci and glycopeptide intermediate-resistant Staphylococcus aureus, as well as teicoplanin-resistant Staphylococcus haemolyticus 3 present a serious global challenge and have led to renewed interest in the development of novel, effective and safe antibacterials including new derivatives of glycopeptide antibiotics. [4][5][6] Inspired by the high activity of the semisynthetic lipoglycopeptide antibiotics telavancin, 7 dalbavancin 8 and oritavancin 9 against vancomycin-resistant bacteria, we have started a program to produce new antibiotics by introducing lipophilic subtituents to the primary amino function of ristocetin aglycon and of teicoplanin pseudoaglycon. Applying various approaches including squaric acid conjugation method, azide-alkyne cycloaddition reaction or three-component isoindole formation, we have prepared a large set of new derivatives exhibiting high antibacterial [10][11][12][13] and, in some cases, robust antiinfluenza virus activity.…”