Targeting quorum sensing signal biosynthesis to fight antibiotic resistant infections: Ambuic acid as a model inhibitor.

Targeting quorum sensing signal biosynthesis to fight antibiotic resistant infections: Ambuic acid as a model inhibitor. Antimicrob Agents Chemother. 2017 Jun 12;: Authors: Todd DA, Parlet CP, Crosby HA, Malone CL, Heilmann KP, Horswill AR, Cech NB Abstract There has been major interest by the scientific community in anti-virulence approaches against bacterial infections. However, partly due to a lack of viable lead compounds, anti-virulence therapeutics have yet to reach the clinic. Here we investigate the development of an anti-virulence lead targeting quorum sensing signal-biosynthesis, a process that is conserved in Gram positive bacterial pathogens. Some preliminary studies suggest that the small molecule ambuic acid is a signal biosynthesis inhibitor. To confirm this, we construct a methicillin-resistant Staphylococcus aureus (MRSA) strain that decouples AIP production from regulation, and demonstrate that AIP production is inhibited in this mutant. Quantitative mass spectrometric measurements show that ambuic acid inhibits signal biosynthesis (IC50 of 2.5 ± 0.1 μM) against a clinically relevant USA 300 MRSA strain. Quantitative real-time PCR confirms that this compound selectively targets the quorum sensing regulon. We show that a 5 μg dose of ambuic acid reduces MRSA-induced abscess formation in a mouse model, and verify its quorum sensing inhibitory activity in vivo Finally, we employ mass spectrometry to identify or conf...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research