Vancomycin Resistance is Overcome by Conjugation of Polycationic Peptides

Multidrug-resistant bacteria represent one of the biggest challenges facing modern medicine. The development of resistances results in an exhaustion of the pool of antibacterial substances, mostly natural products that have been perfected by evolution to a dedicated target. 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. In order 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 1,000-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 the prevalence of a mode of action beyond cell wall inhibition. As further highlight, the antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo efficacy study. Furthermore, molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics. These findings show that medicinal chemistry enables the preservation of seasoned compounds, a fundamentally new approach which avoids the interminable work of de novo antibiotic development.