The rise of antibiotic-resistant bacteria has posed a serious threat to public health. MraY, one of essential enzymes in peptidoglycan biosynthesis, is a promising target for new antibiotics development. MraY is an integral membrane protein that catalyzes the transfer of the monophospho-MurNAc-pentapeptide moiety from Park’s nucleotide (UDP-MurNAc-pentapeptide) onto the undecaprenyl phosphate, to give Lipid I with concomitant release of UMP. In addition, several naturally occurring nucleotide antibiotics have been found to target this bacterial translocase, which allows scientists take advantage of them for scaffold design and structural modification. Taken together, MraY is considered as an attractive and accessible antibacterial druggable target, and without a eukaryotic counterpart.<br/>In our previous work of MraY inhibitor discovery, systematical structural modifications of MraY substrate Park’s nucleotide, were performed to investigate the interactions between moieties of Park nucleotide and MraY enzyme residues. Unexpectedly, one of analogues becomes an inhibitor in an enzyme-based MraY functional assay. However, its MIC value does not show a promising result; presumably, its hydrophilic pyrophosphate moiety might affect its penetration through the bacterial cytoplasmic membrane. In contrast, naturally occurring nucleotide antibiotics don’t contain a pyrophosphate moiety and they might inspire scientists for initial scaffold design, though their complex structures and multi chiral centers might limit their structural diversity and preparation efficiency.<br/>Herein, we would like to develop a flexible synthetic approach to prepare nucleoside derivatives with simplified structures for our MraY inhibition study and antibacterial activity study.

Synthesis of nucleotide-based inhibitors against bacterial cell wall translocase MraY

2019 Fall National Meeting

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