Chemical probes to control a dissociative LuxR-type quorum sensing receptor in Gram-negative bacteria

22 October 2024, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Quorum sensing (QS) allows bacteria to respond to changes in cell density and participate in collective behaviors. Interfering in QS could provide a strategy to block pathogenicity, reduce biofouling, and support biotechnology. Many common Gram-negative bacteria use LuxR-type QS receptors that regulate gene transcription in response to chemical signals, most frequently N-acyl L-homoserine lactones (AHLs). The best-studied LuxR-type receptors operate via an “associative” mechanism — i.e., they dimerize and associate with DNA upon ligand binding. In contrast, members of the less well-studied class of “dissociative” LuxR-type receptors bind DNA in the absence of ligand and dissociate from DNA upon ligand binding. Few chemical tools to modulate dissociative receptors have been identified to date. Such probes could provide new entry into mechanistic studies of LuxR-type QS, as dissociative receptors may be more stable in vitro relative to associative LuxR-type receptors. In this work, we report synthetic modulators of EsaR, a dissociative LuxR-type receptor present in the plant pathogen Pantoea stewartii, based on AHL scaffolds. Compound activity was evaluated using cell-based EsaR reporters and phenotypic assays. We identified specific structural features associated with agonistic activity in EsaR, some of which were comparable to synthetic ligands active in other LuxR-type receptors. In contrast to prior studies of synthetic AHL mimics, no EsaR antagonists were uncovered in our investigations. These results provide chemical strategies to investigate the mechanisms of ligand response in EsaR and suggest that different approaches may be required to develop competitive antagonists for dissociative LuxR-type receptors.

Keywords

Autoinducer
cell-cell communication
chemical probe
N-acyl homoserine lactone
transcription factor
virulence

Supplementary materials

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Supporting Information file
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Additional assay methods and biological data in support of the main text.
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