Abstract
Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d‐Ala‐d‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.
Highlights
Vancomycin is the critical and decisive antibiotic for the treatment of multidrug-resistant infections caused by Grampositive bacteria.[6]
The highly cross-linked heptapeptide core structure of vancomycin minimizes the loss of conformational entropy upon binding, leading to micromolar binding affinities
Vancomycin represents a rare example of a small molecule with the capability of high
Summary
Using sitefor low-molecular weight organic compounds, vancomycin is specific reactions, vancomycin could be modified at four capable of neutralizing the peptide moiety of the cell wall different sites, named VN, VR, VC, and VV (Scheme 2), precursor lipid II.[7] Ever since its discovery in 1958, vanco- resulting, for example, in the compounds FU002, FU007, mycin seemed to be a drug devoid of the threat of resistance FU008 or FU013
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