Design and Synthesis of Carbohydrate Based Derivatives as Antimicrobial Compounds

Abstract

Investigations into the design of analogues of GlcNAc-Ins, the substrate for the enzyme GlcNAc-Ins deacetylase (mshB), a therapeutic target on the pathway to mycothiol biosynthesis in Mycobacterium tuberculosis are described. Initial studies directed towards the design of a substrate analogue were based on the 3-D structure and a proposed mechanism of action of mshB (deduced by Dr. Andrew McCarthy, EMBL). The compounds were designed with the aim to produce an analogue which could better mimic the natural substrate for mshB (GlcNAc-Ins) for crystallisation and mechanistic studies to further improve the knowledge of this enzyme. A series of fatty acid ester and ether derivatives were designed and synthesised based on carbohydrate and non-carbohydrate polyhydroxylated scaffolds with a view to testing their antimicrobial activity against microorganisms of concern to the food and healthcare industries. The synthesised compounds, along with their corresponding fatty acid monoglyceride antimicrobials, were evaluated for antimicrobial activity against Staphylococcus aureus and Escherichia coli. Of the derivatives synthesised several of the carbohydrate based compounds have antimicrobial efficacy comparable with commercially available antimicrobials. The results suggest that the nature of the carbohydrate core plays a role in the efficacy of carbohydrate fatty acid derivatives as antimicrobials.