Attenuation of Quorum Sensing in the Pathogen <i>Acinetobacter baumannii</i> Using Non-native <i>N</i>‑Acyl Homoserine Lactones

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. <i>Acinetobacter baumannii</i> 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 <i>A. baumannii</i> 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. <i>A. baumannii</i> uses <i>N-</i>(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 <i>A. baumannii</i> for use as chemical probes to modulate QS phenotypes in this pathogen. We screened a focused library of synthetic, non-native <i>N</i>-acyl homoserine lactones (AHLs) to identify such compounds, and several highly potent antagonists and agonists were uncovered, with IC₅₀ and EC₅₀ 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 <i>A. baumannii</i> motility, and five antagonists reduced biofilm formation in <i>A. baumannii</i> 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 <i>A. baumannii</i> to be reported and could find utility as new tools to study the role and timing of QS phenotypes in <i>A. baumannii</i> infections