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Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides |
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| Authors: | Florian Umstätter Dr Cornelius Domhan Dr Tobias Hertlein Priv‐Doz Dr Knut Ohlsen Eric Mühlberg Dr Christian Kleist Dr Stefan Zimmermann Dr Barbro Beijer Dr Karel D Klika Prof Dr Uwe Haberkorn Prof Dr Walter Mier Dr Philipp Uhl |
| Institution: | 1. Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany;2. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Germany;3. Institute for Molecular Infection Biology (IMIB), University of Würzburg, Germany;4. Medical Microbiology and Hygiene, Heidelberg University Hospital, Germany;5. German Cancer Research Center (DKFZ), NMR Spectroscopy Analysis Unit, Germany;6. Department of Nuclear Medicine, Heidelberg University Hospital, Germany;7. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Germany;8. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Germany |
| 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. |
| Keywords: | antibiotics bacterial resistance glycopeptide antibiotics peptide conjugates vancomycin |