Ambuic acid is a natural product that targets the quorum sensing pathway of pathogenic Gram-positive bacteria including methicillin resistant <i>Staphylococcus aureus</i> (MRSA), resulting in a decrease of virulence factor production to ultimately reduce bacterial pathogenicity. Ambuic acid is the only compound known to inhibit accessory gene regulator B (AgrB), a transmembrane protein responsible for releasing autoinducing peptides that regulate intercellular quorum sensing. The goal is to synthesize analogues of ambuic acid to enhance its biological activity. The analogues are targeted via semi-synthetic approaches using ambuic acid isolated from the fungus <i>Pestalotiopsis microspora</i> as well as total synthetic approaches that allow for late-stage functionalization. Two total synthetic routes are tackled with each allowing for efficient access to a variety of analogues; one of the routes featuring a regioselective Claisen rearrangement while the other utilizes aldehyde-alkyne reductive coupling to set the stage for relay enyne ring-closing metathesis. Structure-activity relationships will help elucidate the potential role of the diverse functionality present in ambuic acid for inhibition to ultimately obtain the most active analogues against virulence. The research presented describes our current efforts towards the semi-synthetic and total synthetic approaches of ambuic acid analogues.

Synthesis of ambuic acid analogues

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.