A Sub-Micromolar MraYAA Inhibitor with an Aminoribosyl Uridine Structure and a (S,S)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling.

Martin Oliver,Christine Gravier-Pelletier,Ana Amoroso,Bernard Joris,Mélanie Poinsot,Sandrine Calvet-Vitale,Ahmed Bouhss,Laurent Le Corre,Hongwei Wan,Michaël Bosco

doi:10.3390/molecules27061769

Abstract

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraYAA transferase activity, and the most active compound with an original (S,S)-tartaric diamide linker inhibits MraY activity with an IC50 equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.

Highlights

The continuous emergence of bacterial resistance to commonly used antibiotics is a major risk to global health [1–3]
We focused on the synthesis of urea-containing compounds substituents (Figure 2B), and the most active inhibitor (IC50 equal to 1.9 μM) was the one with various substituents
We reported the synthesis of five new inhibitors of the bacterial MraY

Summary

Introduction

The continuous emergence of bacterial resistance to commonly used antibiotics is a major risk to global health [1–3]. It has a significant societal impact, in economic terms, due to the increased length of hospital stays because of nosocomial infections that considerably affects hospital costs [4–7]. The membrane [8] and intracytoplasmic [9] steps of peptidoglycan biosynthesis are underexploited and deserve special attention. Peptidoglycan biosynthesis is a complex process that takes place successively in the cytoplasm, the membrane and the periplasm (Figure 1). The MraY transferase catalyzes the first membrane-associated step of this biosynthesis, namely the transfer of the phospho-MurNAc-pentapeptide moiety

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