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

In 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.