Attenuation of Quorum Sensing in the Pathogen Acinetobacter baumannii Using Non-native N-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. 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 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 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.

Phase-Variable Control of Multiple Phenotypes in Acinetobacter baumannii Strain AB5075

“…However, there were no significant differences in the phase variation frequency in either direction between opaque and translucent variants in the abaI mutant compared to the wild type (data not shown). In addition, a quorum sensing signal produced in an AbaI-dependent manner is 3-OH C 12 -homoserine lactone (3-OH C 12 -HSL) (31,32). The ability of synthetic 10 M 3-OH C 12 -HSL to stimulate phase variation was examined, but no significant differences were observed compared to growth in LB without 3-OH C 12 -HSL ( Table 1).…”

DNA Uptake by the Nosocomial Pathogen Acinetobacter baumannii Occurs during Movement along Wet Surfaces

“…Even though phenotypically distinct, all forms of motility described for A. baumannii have been shown to depend on synthesis of the polyamine 1,3-diaminopropane (26). Surface motility of A. baumannii was further shown to be controlled by blue light sensing (28) and quorum sensing (24,29) and to depend on iron availability (30,31).…”

Acinetobacter baumannii biofilm resistance mechanisms and prevention and control of progress

“…When the number of bacteria reaches a critical level, AHL becomes an effective sensing signal that prompts the production of a large number of intercellular adhesins in the polysaccharides, and the biofilm is formed by embedding the micro-colonies. [23] However, Stacy et al [24] demonstrated that Acinetobacter baumannii used non-N-…”