# Synthesis of New DltA Inhibitors and Their Application as Adjuvant Antibiotics to Re-Sensitize Methicillin-Resistant Staphylococcus aureus

## TL;DR

This paper reports the synthesis of new DltA inhibitors that can re-sensitize methicillin-resistant Staphylococcus aureus to antibiotics.

## Contribution

The study introduces novel DltA inhibitors with improved properties for re-sensitizing MRSA to imipenem.

## Key findings

- Seven new DltA inhibitors showed moderate to excellent IC50 values in vitro.
- Two compounds reduced bacterial cell wall D-alanyl residues by 50% and 80% in vivo.
- These inhibitors effectively re-sensitized MRSA to imipenem.

## Abstract

The synthesis of a new acyclic and cyclic series of D-Ala-AMP analogues was reported. Chemical modifications were introduced on the carbohydrate, the sulfamate linker, and/or the amino-acid N-terminal moiety in order to increase in vivo stability and cell permeability. These new compounds were evaluated in vitro as DltA inhibitors and also in vivo as adjuvant antibiotics to re-sensitize methicillin-resistant Staphylococcus aureus. Indeed, we showed that seven nucleosides containing either a fluorine atom, an azido group, a difluorophosphonylated allylic ether moiety onto the 2′-position, or a sulfamate and a triazole as the sulfamate linker had moderate to excellent IC50 values. Among all these new DltA inhibitors, two molecules functionalized by the fluorinated ether or the sulfamide linker were able to efficiently re-sensitize MRSA to imipenem. Quantification of D-alanyl esters confirmed that these two compounds reduced the level of bacterial cell wall D-alanyl residues by 50% and 80%.