Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

Anna Heib,Christian Ducho,Giuliana Niro,Stefan Koppermann,Stefanie C Weck

doi:10.3390/molecules25010022

Abstract

Muraymycins are a subclass of naturally occurring nucleoside antibiotics with promising antibacterial activity. They inhibit the bacterial enzyme translocase I (MraY), a clinically yet unexploited target mediating an essential intracellular step of bacterial peptidoglycan biosynthesis. Several structurally simplified muraymycin analogues have already been synthesized for structure–activity relationship (SAR) studies. We now report on novel derivatives with unprecedented variations in the nucleoside unit. For the synthesis of these new muraymycin analogues, we employed a bipartite approach facilitating the introduction of different nucleosyl amino acid motifs. This also included thymidine- and 5-fluorouridine-derived nucleoside core structures. Using an in vitro assay for MraY activity, it was found that the introduction of substituents in the 5-position of the pyrimidine nucleobase led to a significant loss of inhibitory activity towards MraY. The loss of nucleobase aromaticity (by reduction of the uracil C5-C6 double bond) resulted in a ca. tenfold decrease in inhibitory potency. In contrast, removal of the 2′-hydroxy group furnished retained activity, thus demonstrating that modifications of the ribose moiety might be well-tolerated. Overall, these new SAR insights will guide the future design of novel muraymycin analogues for their potential development towards antibacterial drug candidates.

Highlights

The increasing number of bacterial infections with strains that are resistant against established antibiotics are a major challenge in current and future clinical healthcare [1,2]
A promising target not yet addressed by clinically established classes of antibiotics is the bacterial enzyme MraY which mediates a key step in the intracellular stages of bacterial cell wall biosynthesis [4,5,6]
The synthesis of nucleosyl amino acids 18–20 was performed in analogy to the previously reported stereocontrolled synthesis of other uridine-derived 5’-deoxy nucleosyl amino acids

Summary

Introduction

The increasing number of bacterial infections with strains that are resistant against established antibiotics are a major challenge in current and future clinical healthcare [1,2]. A promising target not yet addressed by clinically established classes of antibiotics is the bacterial enzyme MraY (translocase I) which mediates a key step in the intracellular stages of bacterial cell wall biosynthesis [4,5,6]. MraY catalyzes the first membrane-associated step in the cytosolic stage of peptidoglycan synthesis, i.e., the formation of the membrane-bound intermediate lipid I by reaction of UDP-MurNAc pentapeptide (’Park’s nucleotide’) with the isoprenoid membrane anchor undecaprenyl phosphate (Scheme 1) [7,8,9,10,11,12,13].

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Discussion

Conclusion