Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant <i>Staphylococcus aureus</i> and Vancomycin-Resistant <i>Enterococci</i>

Lipophilic
substitution on vancomycin is an effective strategy
for the development of novel vancomycin analogues against drug-resistant
bacteria by enhancing bacterial cell wall interactions. However, hydrophobic
structures usually lead to long elimination half-life and accumulative
toxicity; therefore, hydrophilic fragments were also introduced to
the lipo-vancomycin to regulate their pharmacokinetic/pharmacodynamic
properties. Here, we synthesized a series of new vancomycin analogues
carrying various sugar moieties on the seventh-amino acid phenyl ring
and lipophilic substitutions on vancosamine with extensive structure–activity
relationship analysis. The optimal analogues indicated 128–1024-fold
higher activity against methicillin-susceptible S. aureus, vancomycin-intermediate resistant S. aureus (VISA),
and vancomycin-resistant Enterococci (VRE) compared
with that of vancomycin. In vivo pharmacokinetics studies demonstrated
the effective regulation of extra sugar motifs, which shortened the
half-life and addressed concerns of accumulative toxicity of lipo-vancomycin.
This work presents an effective strategy for lipo-vancomycin derivative
design by introducing extra sugars, which leads to better antibiotic-like
properties of enhanced efficacy, optimal pharmacokinetics, and lower
toxicity.