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

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.