Semisynthetic glycopeptide antibiotics

Groesen, E. van (2022)

Doctoral Thesis

Vancomycin is a last-resort antibiotic for the treatment of many Gram-positive bacterial infections, while remaining inactive against Gram-negative strains. Resistance to vancomycin in Gram-positive stains continues to develop. This thesis describes the recent developments in semisynthetically modifying glycopeptide antibiotics to improve their antibacterial activity. Furthermore, the development of several semisynthetic glycopeptide antibiotics are described including the guanidino lipoglycopeptides, the vancomyxins, and the vancomycin-sideromycins. The guanidino lipoglycopeptides are readily synthesized from vancomycin and display potent in vitro and in vivo activity against Gram-positive bacteria, including vancomycin-resistant strains. Assessment of the activity, properties, and mechanism of action of the guanidino lipoglycopeptides shows the potential of these novel glycopeptides to become best-in class. The vancomyxins, which consist of covalently conjugated vancomycin and outer membrane disruptor polymyxin nonapeptide, display enhanced activity against Gram-negative bacterial strains compared to vancomycin monotherapy or co-administration of the two components. The vancomycin-sideromycins are also aimed at conferring antibacterial activity against Gram-negative bacteria by exploiting an iron-uptake system. Overall, a variety of semisynthetic vancomycin derivatives, aimed at overcoming vancomycin resistance or sensitizing Gram-negative strains, are developed and assessed on their activity in this work.

• Vancomycin
• Glycopeptides
• Gram-positive
• Gram-negative
• Guanidino
• Semisynthesis
• Antimicrobial resistance
• Lipid II
• Cell wall biosynthesis inhibitor
• Methicillin-resistant S. aureus

• All authors: Groesen, E. van
• Supervisor: Martin, N.I.; Stelt, M. van der
• Committee: Wezel, G.P. van; Briegel, A.; Overkleeft, H.S.; Weingarth, M.H.; Scheffers, D.J.
• Qualification: Doctor (dr.)
• Awarding Institution: Institute of Biology Leiden (IBL), Faculty of Science, Leiden University
• Date: 2022-10-12