Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures.

Anatol Spork,Stephanie Schier (Née Wohnig),Stefan Koppermann,Christian Ducho,Ruth Linder

doi:10.3390/molecules23112868

Anatol Spork, Stephanie Schier (Née Wohnig) + Show 3 more

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https://doi.org/10.3390/molecules23112868

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Abstract

Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products. As part of detailed structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5′,6′-anti-configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates.

Highlights

Infections with bacterial strains that have developed resistance against clinically used antibiotics are on the rise and represent a major challenge in healthcare [1,2]
For the sake of efficiency, we have decided to pursue a bipartite strategy in this work as most of the structural variations would be in the nucleoside pursue a bipartite strategy in this work as most of the structural variations would be in the nucleoside core
The dissection of target target structures 10–17 into two principle building blocks led to the protected urea tripeptide 18 and structures 10–17 into two principle building blocks led to the protected urea tripeptide 18 and aminoalkylated nucleosyl amino acids 19–22 (Scheme 2)

Summary

Introduction

Infections with bacterial strains that have developed resistance against clinically used antibiotics are on the rise and represent a major challenge in healthcare [1,2]. New targets and new modes of action are needed to fight back such infections. Such novel targets can be found in bacterial pathways that have already been addressed by many antibiotics [3]. MraY (translocase I) represents an example of a yet unexploited target, as it is part of bacterial peptidoglycan biosynthesis, i.e., one of the main pathways addressed by established antibiotics [4,5]. MraY catalyses the first membrane-associated step of peptidoglycan formation: the reaction of UDP-MurNAc pentapeptide (‘Park’s nucleotide’) 1 with the isoprenoid membrane anchor undecaprenyl phosphate 2, yielding membrane-bound lipid I 3 (Scheme 1) [6,7,8,9,10,11,12].

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