Developing polyketide‐based anti‐microbial therapeutics using synthetic enzymology

Abstract

Enterococcus faecalis is an example of a bacterium that has gained multi‐drug resistance and is a major cause of nosocomial infections. In this project, we are targeting the enzymes present in the shikimate pathway within E. faecalis, as this pathway is absent in humans and crucial to the microbe, making the pathway an attractive target for drug design. A preliminary screen using a limited compounds library was performed on two enzymes present within the shikimate pathway and several potential inhibitors bearing the polyketide scaffold were identified. Polyketides are a large class of natural biomolecules biosynthesized from acyl‐CoA precursors using polyketide synthases (PKSs) that includes clinically important antibiotics such as tetracycline. Our project focuses on an uncharacterized Type III PKS, a putative chalcone synthase, from Oryza sativa (OsCHS). In order to produce a chemically diverse library of polyketides, a precursor‐directed biosynthesis approach was employed whereby different acyl‐CoA esters were tested as possible substrates for OsCHS and the enzyme was found to be promiscuous. The results suggested that the synthesis of novel compounds using synthetic enzymology was feasible and these polyketides could be used to screen for inhibitory activity against E. faecalis shikimate pathway enzymes to identify lead compounds for future antibiotic drug development.