In the antibiotics arsenal, vancomycin is alast resort for the treatment of intractable infections.H owever,t his situation is under threat because of the increasing appearance of vancomycin-resistant bacteria (VRB). Herein, we report aseries of novel vancomycin derivatives carrying asulfonium moiety.T he sulfonium-vancomycin derivatives exhibited enhanced antibacterial activity against VRB both in vitro and in vivo.T hese derivatives also exhibited activity against some Gram-negative bacteria. The sulfonium modification enhanced the interaction of vancomycin with the bacterial cell membrane and disrupts membrane integrity.Furthermore, the in vivo pharmacokinetic profile,s tability,a nd toxicity of these derivatives demonstrated good druggability of the sulfonium-vancomycin analogues.This work provides apromising strategy for combating drug-resistant bacterial infection, and advances the knowledge on sulfonium derivatives for structural optimization and drug development.

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.

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