In the search for suitable S1 binding fragments of SARS-CoV-2 Mpro, pyridine-electrophile combinations with different linkers (L, X) were tested regarding their activity, kinetics and chemical stability. Halopyridinyl esters sho...
Single Modification at the N‐Terminus of Norvancomycin to Combat Drug‐Resistant Gram‐Positive Bacteria
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The introduction of an optimal single modification at the N-terminus of norvancomycin, especially an aromatic-sulfonium moiety, endowed the parent norvancomycin with 16- to 2048-fold enhancement in antibacterial activity against vancomycin-resistant bacteria. This facilitated the enrichment of diversity of N-terminal modifications for norvancomycin and benefited the corresponding extensive structure–activity relationship summary.
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.Zum Volltext
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