Single Modification at the N‐Terminus of Norvancomycin to Combat Drug‐Resistant Gram‐Positive Bacteria

Author:

Guan Dongliang12ORCID,Chen Feifei3,Shi Wei14,Lan Lefu536ORCID,Huang Wei1564ORCID

Affiliation:

1. CAS Key Laboratory of Receptor Research CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Materia Medica Chinese Academy of Sciences 555 Zuchongzhi Road, Pudong Shanghai 201203 P. R. China

2. Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug Discovery Yantai Shandong 264117 P. R. China

3. State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 P. R. China

4. Center for Biotherapeutics Discovery Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 P. R. China

5. School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou 310024 P. R. China

6. University of Chinese Academy of Sciences No.19 A Yuquan Road Beijing 100049 P. R. China

Abstract

AbstractIn the arsenal of glycopeptide antibiotics, norvancomycin, which differs from vancomycin by a single methyl group, has received much less attention. Facing the risks of serious antibiotic resistance and even the collapse of last‐line defenses, we designed and synthesized 40 novel norvancomycin derivatives to combat the threat. 32 compounds are single N‐terminally modified derivatives generated through simple and efficient methods. Diversity at the N‐terminus was greatly enriched, mainly by lipophilic attachment and strategies for the introduction of lipo‐sulfonium moieties for extensive structure–activity relationship analysis. The first incorporation of a sulfonium moiety into the norvancomycin structure gave rise to compounds that exhibited 4‐ to 2048‐fold higher activity against vancomycin‐resistant bacteria VISA and VRE. This N‐terminal modification for norvancomycin provides an alternatively useful and promising strategy to restore the antibacterial activity of glycopeptide antibiotics against resistant bacteria, highlighting the same importance of the N‐terminal site as well as the vancosamine position, which is worth further study and development.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

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