10.1002/anie.201902210
Angewandte Chemie International Edition
COMMUNICATION
compared to vancomycin and thioethers (Fig. 3B and S5). Based
on these data, we proposed a possible MOA of lipo-sulfonium-
vancomycin derivatives as shown in Fig. 3C. As the vancomycin
skeleton approaches bacterial cell wall, sulfonium cationic ion
interacts with the negative charges on bacterial membrane while
the hydrophobic aliphatic tail inserts into the bilayer. The
enhanced interaction between lipo-sulfonium moiety and
membrane of vancomycin-resistant bacteria may result in
disruption of membrane integrity and cell lysis, thus causing
bacterial death.
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In summary, we present a new strategy of sulfonium modification
for vancomycin-based structure optimization, which alters the
antibacterial profile of vancomycin against multi-drug resistant
bacteria and demonstrates good druggable properties of
pharmacokinetics, stability, toxicity, and MOA. This strategy
represents a rational, effective, and promising design of sulfonium
derivatives which was underestimated in medicinal chemistry. In
a practical application, sulfonium-vancomycin compounds enable
disruption of bacterial membrane to tackle the crisis of drug-
resistant bacterial infection, including both Gram-positive and
Gram-negative bacteria resistant to vancomycin. The optimal PK
and safety property of sulfonium derivative also render it a
prospective candidate for further development.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NNSFC, No. 21572244, 21877116),
National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program” of China (No.
2018ZX09711002-006), and the Youth Innovation Promotion
Association of CAS (No. 2017328). We thank Dr. Houchao Tao,
Dr. Fei Zhao in ShanghaiTech University and Dr. Jingjing Shi in
SIMM for their kind help in MS determination.
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Keywords: sulfonium• vancomycin • antibacterial • multi-drug
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