Attenuation of Quorum Sensing in the Pathogen Acinetobacter baumannii Using Non-native N-Acyl Homoserine Lactones

• Type of Material: Article
• Authors: Danielle M. Stacy, University of Wisconsin-Madison; Michael A. Welsh, University of Wisconsin-Madison; Phil N Rather, Emory University; Helen E. Blackwell, University of Wisconsin-Madison
• Language: English
• Date: 2012-10-19
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/cb300351x
• Title of Journal or Parent Work: ACS Chemical Biology
• ISSN: 1554-8929
• Volume: 7
• Issue: 10
• Start Page: 1719
• End Page: 1728
• Grant/Funding Information: The NIH (AI063326), ONR (N00014-07-1-0255), Greater Milwaukee Foundation Shaw Scientist Program, Burroughs Wellcome Fund, and Johnson & Johnson provided generous financial support for this work.; D.M.S. was funded in part by an NSF Graduate Fellowship (DGE-0718123).
• Keywords: Science & Technology; BIOFILM FORMATION; BIOLOGICAL EVALUATION; Biochemistry & Molecular Biology; TO-CELL COMMUNICATION; AUTOINDUCER SYNTHASE; MODULATORS; ASYMMETRIC HYDROGENATION; DRY SURFACES; PSEUDOMONAS-AERUGINOSA; SYNTHETIC LIGANDS; BACTERIA; Life Sciences & Biomedicine
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry; Health Sciences, Immunology

Abstract

Many bacterial pathogens use quorum sensing (QS) to control virulence. As a result, the development of methods to intercept QS has attracted significant interest as a potential anti-infective therapy. Acinetobacter baumannii has emerged as a pan-drug-resistant pathogen and displays a remarkable ability to persist in hospital settings despite desiccation and antimicrobial treatment. Recent studies have shown that A. baumannii QS mutants have limited motility and fail to form mature biofilms; these phenotypes are linked to its ability to persist on biotic and abiotic surfaces and increase its pathogenicity. A. baumannii uses N-(3-hydroxydodecanoyl)-l-homoserine lactone (OH-dDHL) and its putative cognate receptor, AbaR, for QS. We sought to identify non-native ligands capable of blocking or promoting AbaR activity in A. baumannii for use as chemical probes to modulate QS phenotypes in this pathogen. We screened a focused library of synthetic, non-native N-acyl homoserine lactones (AHLs) to identify such compounds, and several highly potent antagonists and agonists were uncovered, with IC < inf > 50 < /inf > and EC < inf > 50 < /inf > values in the low micromolar range, respectively. The strongest AbaR antagonists largely contained aromatic acyl groups, whereas the AbaR agonists closely resembled OH-dDHL. Notably, the 10 most potent AbaR antagonists also strongly inhibited A. baumannii motility, and five antagonists reduced biofilm formation in A. baumannii by up to 40%. The discovery of these compounds is significant, as they represent, to our knowledge, the first non-native modulators of QS in A. baumannii to be reported and could find utility as new tools to study the role and timing of QS phenotypes in A. baumannii infections.