Aug 2026· Annual Review of Microbiology· 0 citations
Medicine
TL;DR
Recent structural and mechanistic insights into LuxR-type receptor function are summarized, including interactions with small molecules, protein partners, and DNA, including interactions with small molecules, protein partners, and DNA.
Abstract
Quorum sensing (QS) enables bacteria to coordinate collective behaviors in response to population density. LuxI/R QS systems, common among gram-negative bacteria, consist of a LuxI-type synthase that produces an N-acyl L-homoserine lactone (AHL) signaling molecule and a LuxR-type receptor that senses the AHL. At threshold AHL concentrations, LuxR-type receptors undergo ligand-induced conformational changes that affect DNA binding and target gene transcription. Because of their role in regulating myriad collective behaviors, LuxI/R systems are targets for many applications, including antivirulence strategies and the engineering of beneficial microbiomes. Recent structural studies have led to substantial progress in understanding molecular mechanisms of LuxI/R systems. However, LuxR-type receptors fall into functionally diverse subfamilies for which structural bases remain incompletely understood. In this article, we summarize recent structural and mechanistic insights into LuxR-type receptor function, including interactions with small molecules, protein partners, and DNA. We identify critical knowledge gaps that highlight the need for additional structural and mechanistic information regarding LuxI/R QS.
LuxI/R quorum sensing controls diverse cell density-dependent behaviors in gram-negative bacteria, yet the molecular basis of LuxR-type receptor response to ligands remains poorly defined. This gap limits both mechanistic understanding of signaling and the rational design of synthetic LuxR modulators. LuxR homologues exhibit two response modes: associative receptors require N-acyl l-homoserine lactone (AHL) signal binding to enable DNA binding and transcriptional activation, whereas dissociative receptors are active without ligand and inhibited upon AHL binding. Herein, we dissect determinants of ligand-response type using domain swapping and mutagenesis across four archetypical receptors: the associative receptors LasR (Pseudomonas aeruginosa) and MrtR (Mesorhizobium tianshanense), and the dissociative receptors EsaR (Pantoea stewartii) and ExpR2 (Pectobacterium versatile). Analyses of domain-swapped receptors revealed that the ligand-binding domain largely dictates associative versus dissociative behavior in response to native AHL agonists. Consistently, non-native AHL-derived antagonists retained their activity when DNA-binding domains were interchanged, underscoring the primacy of the ligand-binding module. We also found that the extended interdomain linker characteristic of dissociative receptors does not determine response mechanism. Instead, our data implicate receptor-specific interdomain interactions in activation. Notably, deletion of a single residue in EsaR converted this dissociative receptor into an associative one, representing, to our knowledge, the first example of such a mechanistic inversion in a LuxR-type protein. Together, these findings define key structural features governing ligand response and reveal unexpected mechanistic plasticity, providing a foundation for more informed design of next-generation quorum sensing modulators with enhanced specificity, potency, and predictable activity across diverse receptors.
Irene M. Stoutland, Susan Walker, Helen E. Blackwell· Journal of the American Chem...· 0 citations
Many bacteria engage in quorum sensing (QS), a cell-cell communication system used to coordinate group behaviors. In one type of QS, acyl-homoserine lactone signals generated by LuxI homologs bind to LuxR homolog transcription factors, usually resulting in gene activation. The genome of Pseudomonas aeruginosa encodes three such LuxR homologs: LasR, RhlR, and QscR. Of these, LasR regulates the most genes, including that encoding RhlR. There is strong evidence that, during chronic infections, lasR and other genes encoding LuxR-type regulators are under strong selective pressure for mutations that both inactivate and modulate their function. Thus, we wondered if some mutations in the lasR gene might result in a protein with affinity for promoters usually regulated by the other LuxR homologs; to do so, we investigated the DNA-binding domain (DBD) of LasR through alanine substitution. As expected, we found that most alanine substitutions across the LasR DBD led to loss of function, as did previously identified clinical LasR DBD variants. Additionally, some alanine mutants were indistinguishable from the wild type. We describe a handful of variant LasR polypeptides that unexpectedly exhibit enhanced regulation on a RhlR-regulated gene, which conferred a fitness defect when competed against the wild type. Most other LasR variants had a competitive advantage. Our results suggest a pathway for expansion of the regulon of LuxR-homolog transcription factors, but also that such mutations may be disfavored due to the incurred metabolic burden. Importance Many bacteria generate chemical signals to alter gene expression in response to changes in population density, a phenomenon called quorum sensing. One type of quorum sensing relies on acyl-homoserine lactone (AHL) signals. In this type of quorum sensing, first described in the bioluminescent bacterium Vibro fisheri, a LuxI homolog produces the AHL, which binds to a LuxR homolog that typically activates gene expression. The opportunistic pathogen Pseudomonas aeruginosa has two such LuxR homologs, LasR and RhlR, each of which has its own specific regulon. We focused on the transcription factor LasR and investigated structural determinants of its binding to target promoters using an alanine substitution approach. We discovered that some DNA-binding mutations can expand the range of LasR-regulated genes. Our work provides insight into understanding what promoters LuxR homologs bind to and, more generally, how these proteins might evolve over time to change the group of genes that they regulate.
Zichu Yang, A. Billa, Aditya S. Desai et al.· bioRxiv· 0 citations
This review highlights recent advances in the development of sulfonyl- and sulfinyl-containing organosulfur compounds as modulators of QS and biofilm formation in clinically relevant Gram-negative pathogens.
D. Nwobodo, M. Egbujor, Samuel S. Kiprotich et al.· FEMS Microbiology Reviews· 0 citations
Findings suggest that Withaferin A and Obacunone could serve as promising therapeutic agents against H. pylori infections by disrupting quorum sensing and biofilm formation, thus addressing the challenge of antibiotic resistance in this pathogen.
Thejaswi Bhat, Manish Kumar, T. Gnanasekaran et al.· Biologia· 0 citations
This study provides novel and unexpected insights into the involvement of a LuxR homolog in regulating a QS system in Gram-positive bacteria and demonstrates that functional GBL-based QS systems are conserved and active in R. erythropolis.
Héloïse Bizière-Maco, Nathan Jordier, J. F. Barbosa-de-Bessa et al.· Frontiers in Microbiology· 0 citations
ABSTRACT Quorum sensing (QS) enables microorganisms—including bacteria, eukaryotes, and viruses—to coordinate collective behaviors in response to population density. Despite their ecological and evolutionary significance, QS mechanisms in Archaea remain poorly characterized. The halophilic archaeon Haloferax volcanii provides a model for archaeal QS, transitioning from motile rods to non-motile disks in a density-dependent response to a secreted disk-forming signal (DFS). To identify components of the DFS regulatory network, we screened for spontaneous mutants that retained motility in DFS-containing soft-agar medium. One candidate, HVO_1357, encodes a predicted response regulator located adjacent to a histidine kinase (HVO_1356) and a second response regulator (HVO_1358), consistent with an extended two-component regulatory system (TCS). Based on our results, these genes encode quorum-sensing-associated regulators (Qar); therefore, we propose renaming them to qarA (HVO_1357), qarB (HVO_1356), and qarC (HVO_1358). Deletion of qarA enabled cells to swim on DFS-containing soft-agar plates and conferred hypermotility on standard soft-agar media; however, these phenotypes were not due to changes in motility-related parameters, but a reduced sensitivity to DFS for induction of the non-motile, disk-shaped state. In contrast, ΔqarB and ΔqarC strains were non-motile and exhibited premature disk formation during normal growth. Suppressor mutations restoring motility to ΔqarB and ΔqarC mapped exclusively to qarA, and epistasis analysis indicated QarA as the central regulator of this system. Phosphoablative variants of QarA, QarB, and QarC failed to complement their respective deletion strains, supporting QarABC as a TCS. Transcriptomic analyses revealed that qarA deletion leads to upregulation of genes involved in motility and rod-shape formation. Together, these findings reveal qarABC as a DFS-responsive regulatory module and represent the first TCS in archaea shown to control QS-dependent behavior. IMPORTANCE Archaea are ubiquitous and play key roles across diverse ecosystems—including human microbiomes—yet little is known about how they communicate with one another and with other organisms, or how these interactions shape their ecological impact. Such intercellular communication, including quorum sensing (QS), allows microorganisms to coordinate behaviors critical for survival, adaptation, and community organization. In this study, we identify the first archaeal two-component regulatory system that is involved in QS-dependent regulation, providing a foundation for understanding how organisms in this domain sense and respond to population cues. By revealing a previously unknown aspect of archaeal biology, this work represents an important step toward understanding how archaeal communication shapes both their physiology and their interactions within complex microbial communities. Archaea are ubiquitous and play key roles across diverse ecosystems—including human microbiomes—yet little is known about how they communicate with one another and with other organisms, or how these interactions shape their ecological impact. Such intercellular communication, including quorum sensing (QS), allows microorganisms to coordinate behaviors critical for survival, adaptation, and community organization. In this study, we identify the first archaeal two-component regulatory system that is involved in QS-dependent regulation, providing a foundation for understanding how organisms in this domain sense and respond to population cues. By revealing a previously unknown aspect of archaeal biology, this work represents an important step toward understanding how archaeal communication shapes both their physiology and their interactions within complex microbial communities.
Jacob A. Cote, Priyanka Chatterjee, Marco Garcia et al.· mBio· 1 citation
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