Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

Abstract

The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine’s capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.

Emerging Target-Directed Approaches for the Treatment and Diagnosis of Microbial Infections

“…Notable examples are the vancomycin analogues with guanidium modifications reported by Wu et al that showed enhanced activity against resistant strains of S. aureus . Additionally, an overview of the recent advances regarding a wide range of vancomycin analogues can be found in the review article by van Groesen et al for further information on this subject.…”

“…Notable examples are the vancomycin analogues with guanidium modifications reported by Wu et al 197 that showed enhanced activity against resistant strains of S. aureus. Additionally, an overview of the recent advances regarding a wide range of vancomycin analogues can be found in the review article by van Groesen et al 198 for further information on this subject. Compounds 88−90 (Figure 45) are part of a series of porphyrin conjugates with lysins which showed potential as photodynamic antimicrobials that are active after irradiation.…”

A comprehensive review of microorganism‐derived cyclic peptides: Bioactive functions and food safety applications

“…They disrupted the bacterial membrane integrity and lead to cell death finally by binding to the lipid A moiety of lipopolysaccharides (Wang et al., 2022). In the 1950s, vancomycin, a cyclic glycopeptide antibiotic isolated from microbial fermentation of Borneo soil, was found to have an inhibitory effect on penicillin‐resistant strains (van Groesen et al., 2022). The antimicrobial mechanism of vancomycin is the combination of its N‐terminal and D‐Ala‐D‐Ala residues in the C‐terminal of a peptidoglycan precursor (van Groesen et al., 2022).…”

“…In the 1950s, vancomycin, a cyclic glycopeptide antibiotic isolated from microbial fermentation of Borneo soil, was found to have an inhibitory effect on penicillin‐resistant strains (van Groesen et al., 2022). The antimicrobial mechanism of vancomycin is the combination of its N‐terminal and D‐Ala‐D‐Ala residues in the C‐terminal of a peptidoglycan precursor (van Groesen et al., 2022). Because the peptidoglycan precursor locates at the outer surface of the bacterial cell plasma membrane, their binding precludes its transpeptidation reaction and inhibits the synthesis of the bacterial cell walls (Figure 3a).…”

Organocatalytic Activation of Inert Hydrosilane for Peptide Bond Formation

“…In addition, a survey conducted by three major pharmaceutical companies in 2006 revealed that two-thirds of drug candidates contain an amide group . Furthermore, medium-sized amide molecules like peptides and glycopeptides have recently attracted considerable attention as important targets in the discovery of novel drugs . In light of this growing demand for amide molecules, the ACS Green Chemistry Institute Pharmaceutical Roundtable included the goal to develop “general methods for catalytic/sustainable (direct) amide or peptide formation” as one of the 10 key green chemistry research areas in 2018 …”