Impact of Linker Modification and PEGylation of Vancomycin Conjugates on Structure-Activity Relationships and Pharmacokinetics.

Florian Umstätter,Tobias Hertlein,Julia Werner,Philipp Uhl,Uwe Haberkorn,Knut Ohlsen,Leah Zerlin,Walter Mier,Barbro Beijer,Christian Kleist,Stefan Zimmermann,Cornelius Domhan,Karel D Klika,Eric Mühlberg

doi:10.3390/ph15020159

Abstract

As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.

Highlights

Multidrug-resistant bacteria have become an unpredictable burden
In the previous study [11], the secondary amine of vancomycin was found to be the preferred modification site for antimicrobial activity; all conjugates were coupled at this position in the present study
The synthesized substances showed activity in microdilution assays, not all derivatives showed the ability to overcome the resistance breakpoint of vancomycin in vancomycin-resistant strains. These findings clearly demonstrate the importance of spacer length between vancomycin and its polycationic peptide modification for retaining antimicrobial efficacy, as well as the fact that a defined spatial structure is needed to maintain antimicrobial activity

Summary

Introduction

Multidrug-resistant bacteria have become an unpredictable burden. By 2050, worldwide, up to 10 million deaths might be caused by bacterial pathogens [1]. The development of effective antimicrobial substances should be expedited to counter this threat [2]. Non-academic research stagnates, and most pharmaceutical companies have abandoned antibiotic development [3,4]. Some encouraging developments have been made recently in the academic sector. Due to the immense financial costs of de novo developments, modification of established substances has become a key strategy

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