Model for Antibiotic Optimization via Neoglycosylation:  Synthesis of Liponeoglycopeptides Active against VRE

Abstract

The neoglycosylation of a methoxyamine-appended vancomycin aglycon with all possible N'-decanoylglucopyranose and N'-biphenoylglucopyranose regioisomers led to the production of a focused set of liponeoglycopeptide variants in good yields and with excellent stereoselectivity. High-throughput antibacterial assays employing a unique set of vancomycin-resistant Enterococci faecalis and Enterococci faecium clinical isolates revealed that the nature and regiochemistry of glycosyl lipidation modulated vancomycin-resistent Enterococci potency. In contrast to prior work with lipoglycopeptides, this study reveals the glucose C3' or C4' as the optimal position for neoglycopeptide lipidation. This purely chemical method for the diversification of the glycolipid portion of lipoglycopeptide antibiotics is simple to perform on a large scale, requires minimal synthetic effort in sugar donor preparation, and provides access to highly active antibiotics that are not easily prepared by other state-of-the-art methods.

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

“…FT-MALDI Lipo-neo-glycopeptides Neoglycosylation of methoxyamineappended vancomycin aglycon (Griffith, et al, 2007) O-Mannosylated peptides (fluorescently labelled) TOF, ESI As components for synthetic vaccines: comparison of two synthetic strategies (Brimble, et al, 2008) MUC1 Glycopeptides L-, R-TOF (DHB)…”

Structure Diversification of Vancomycin through Peptide-Catalyzed, Site-Selective Lipidation: A Catalysis-Based Approach To Combat Glycopeptide-Resistant Pathogens

“…48 Since vancomycin is readily available from commercial sources, we synthesized 3 on multi-gram scale (15 g) via a sequential formation of alloc-carbamates, ally-ester and allyl-ethers. 15,48,49 From our initial screening, we found that symmetric anhydrides worked well for the acyl-transfer reactions; while acyl chlorides showed unselective reactivity and N -hydroxysuccinimide active esters were not reactive under the reaction conditions.…”

Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

“…86 The latest variant of the tetracycline class, tigecycline, incorporates a glycyl linker at C9 of 9-aminodoxycycline reminiscent to that used in neoglycosylation strategies toward betulinic acid, 15 colchicine, 20 and vancomycin. 21 A four-step scheme was used to nitrate and attach methoxyglycine to the doxycycline scaffold followed by neoglycosylation with 31 different sugars ( 14 , see Table 3). 26 To extend the study of neoglycosylation, aminosugars were also used, which marks the first instance of these sugars being systematically employed in neoglycosylation.…”

“…21 Based on the structure of the related teicoplanin antibiotic, the natural disaccharide of vancomycin was replaced with 2-,3-,4-, or 6- N -decanoyl or biphenoyl D-glucose using a methoxyaminoethyl tether at the phenol of the vancomycin aglycon ( 15 ). Resulting testing against 15 VRE strains of varying resistance found that alteration of the sugar moiety improved activity against VRE strains with the 3- and 4-acylated sugars identified as the best sugars in this context.…”