Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci.

Eric Mühlberg,Florian Umstätter,Cornelius Domhan,Andreas Krause,Barbro Beijer,Knut Ohlsen,Uwe Haberkorn,Tobias Hertlein,Christian Kleist,Philipp Uhl,Stefan Zimmermann,Walter Mier

doi:10.3390/ph13060110

Abstract

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.

Highlights

An increasing number of antibiotic-resistant bacterial strains are frequently being reported all over the world [1]
A strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed
All conjugates used to determine the influence of varying fatty acid chain lengths could be readily synthesized in sufficient amounts for subsequent experiments in this study

Summary

Introduction

An increasing number of antibiotic-resistant bacterial strains are frequently being reported all over the world [1]. Since the beginning of the 20th century, the mortality rate of bacterial infectious diseases in the United States of America has decreased significantly [5]. This trend can be associated with the discovery of the β-lactam antibiotic penicillin in 1928 and more than 20 other classes of antibiotics thereafter, which have been designed and approved [5,6,7,8]

Methods

Results

Conclusion