Sensing of autoinducer-2 by functionally distinct receptors in prokaryotes.
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ABSTRACT:
SUBMITTER: Zhang L
PROVIDER: S-EPMC7584622 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Quorum sensing (QS) is a mechanism of chemical communication that bacteria use to monitor cell-population density and coordinate group behaviors. QS relies on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. Vibrio cholerae employs parallel QS circuits that converge into a shared signaling pathway. At high cell density, the CqsS and LuxPQ QS receptors detect the intra-genus and inter-species autoinducers CAI-1 and AI-2, respectively, to repress virulence factor production and biofilm formation. We show that positive feedback, mediated by the QS pathway, increases CqsS but not LuxQ levels during the transition into QS-mode, which amplifies the CAI-1 input into the pathway relative to the AI-2 input. Asymmetric feedback on CqsS enables responses exclusively to the CAI-1 autoinducer. Because CqsS exhibits the dominant QS signaling role in V. cholerae, agonism of CqsS with synthetic compounds could be used to control pathogenicity and host dispersal. We identify nine compounds that share no structural similarity to CAI-1, yet potently agonize CqsS via inhibition of CqsS autokinase activity.
| S-EPMC5467912 | biostudies-literature
Project description:Clonal bacterial populations respond to unfavorable conditions with growth arrest and 20 persistence. Here we show that quorum sensing (QS) determines functionally distinct subpopulations of non-growing, virulent Legionella. QS increases the fraction of bacteria re- initiating growth in microcolonies, while it restricts the ratio of bacteria resuming growth in free- living protozoan predators. QS continues to govern the population heterogeneity throughout growth. Intracellular non-growers and growing bacteria are characterized by distinct proteomes 25 reflecting different stress and drug tolerance as well as alternative metabolic pathways. Strikingly, individual intracellular non-growers are persisters, which endure host killing mechanisms, produce virulence factors, form a replication-permissive compartment, and are highly infectious. Thus, QS underlies a bet-hedging strategy of non-growing intracellular bacterial pathogens to resume growth and to fine-tune virulence.
2019-11-19 | PXD015106 | Pride
Project description:Bacterial drug resistance caused by overuse and misuse of antibiotics is common, especially in clinical multispecies infections. It is of great significance to discover novel agents to treat clinical bacterial infections. Studies have demonstrated that autoinducer-2 (AI-2), a signal molecule in quorum sensing (QS), plays an important role in communication among multiple bacterial species and bacterial drug-resistance. Previously, 14 AI-2 inhibited compounds were selected through virtual screening by using the AI-2 receptor protein LuxP as a target. Here, we used Vibrio harveyi BB170 as a reporter strain for the preliminary screening of 14 inhibitors and compound Str7410 had higher AI-2 QS inhibition activity (IC50 = 0.3724 ± 0.1091 μM). Then, co-culture of Pseudomonas aeruginosa PAO1 with Staphylococcus aureus ATCC 25923 was used to evaluate the inhibitory effects of Str7410 on multispecies infection in vitro and in vivo. In vitro, Str7410 significantly inhibited the formation of mixed bacterial biofilms. Meanwhile, the combination of Str7410 with meropenem trihydrate (MEPM) significantly improved the susceptibility of mixed-species-biofilm cells to the antibiotic. In vivo, Str7410 significantly increased the survival rate of wild-type Caenorhabditis elegans N2 co-infected by P. aeruginosa PAO1 and S. aureus ATCC 25923. Real-time quantitative PCR analysis showed that Str7410 reduced virulence factor (pyocyanin and elastase) production and swarming motility of P. aeruginosa PAO1 by downregulating the expression of QS-related genes in strain PAO1 in co-culture with S. aureus ATCC 25923. Compound Str7410 is a candidate agent for treating drug-resistant multispecies infections. The work described here provides a strategy for discovering novel antibacterial drugs.
| S-EPMC8996156 | biostudies-literature
Project description:Functional classification of genes represents a fundamental problem to many biological studies. Most of the existing classification schemes are based on the concepts of homology and orthology, which were originally introduced to study gene evolution but might not be the most appropriate for gene function prediction, particularly at high resolution level. We have recently developed a scheme for hierarchical classification of genes (HCGs) in prokaryotes. In the HCG scheme, the functional equivalence relationships among genes are first assessed through a careful application of both sequence similarity and genomic neighborhood information; and genes are then classified into a hierarchical structure of clusters, where genes in each cluster are functionally equivalent at some resolution level, and the level of resolution goes higher as the clusters become increasingly smaller traveling down the hierarchy. The HCG scheme is validated through comparisons with the taxonomy of the prokaryotic genomes, Clusters of Orthologous Groups (COGs) of genes and the Pfam system. We have applied the HCG scheme to 224 complete prokaryotic genomes, and constructed a HCG database consisting of a forest of 5339 multi-level and 15 770 single-level trees of gene clusters covering approximately 93% of the genes of these 224 genomes. The validation results indicate that the HCG scheme not only captures the key features of the existing classification schemes but also provides a much richer organization of genes which can be used for functional prediction of genes at higher resolution and to help reveal evolutionary trace of the genes.
| S-EPMC1874638 | biostudies-literature
Project description:The human pathogen Pseudomonas aeruginosa coordinates the expression of virulence factors using quorum sensing, a signaling cascade triggered by the activation of signal receptors by small-molecule autoinducers. These homoserine lactone autoinducers stabilize their cognate receptors and activate their functions as transcription factors. Because quorum sensing regulates the progression of infection and host immune resistance, significant efforts have been devoted toward the identification of small molecules that disrupt this process. Screening efforts have identified a class of triphenyl compounds that are structurally distinct from the homoserine lactone autoinducer, yet interact specifically and potently with LasR receptor to modulate quorum sensing (Muh et al., 2006a). Here we present the high-resolution crystal structures of the ligand binding domain of LasR in complex with the autoinducer N-3-oxo-dodecanoyl homoserine lactone (1.4 A resolution), and with the triphenyl mimics TP-1, TP-3, and TP-4 (to between 1.8 A and 2.3 A resolution). These crystal structures provide a molecular rationale for understanding how chemically distinct compounds can be accommodated by a highly selective receptor, and provide the framework for the development of novel quorum-sensing regulators, utilizing the triphenyl scaffold.
| S-EPMC2778763 | biostudies-literature
Project description:Although a variety of bacterial species have been reported to use the interspecies communication signal autoinducer-2 (AI-2) to regulate multiple behaviors, the molecular mechanisms of AI-2 recognition and signal transduction remain poorly understood. To date, two types of AI-2 receptors have been identified: LuxP, present in Vibrio spp., and LsrB, first identified in Salmonella enterica serovar Typhimurium. In S. Typhimurium, LsrB is the ligand binding protein of a transport system that enables the internalization of AI-2. Here, using both sequence analysis and structure prediction, we establish a set of criteria for identifying functional AI-2 receptors. We test our predictions experimentally, assaying key species for their abilities to import AI-2 in vivo, and test their LsrB orthologs for AI-2 binding in vitro. Using these experimental approaches, we were able to identify AI-2 receptors in organisms belonging to phylogenetically distinct families such as the Enterobacteriaceae, Rhizobiaceae, and Bacillaceae. Phylogenetic analysis of LsrB orthologs indicates that this pattern could result from one single origin of the functional LsrB gene in a gammaproteobacterium, suggesting possible posterior independent events of lateral gene transfer to the Alphaproteobacteria and Firmicutes. Finally, we used mutagenesis to show that two AI-2-interacting residues are essential for the AI-2 binding ability. These two residues are conserved in the binding sites of all the functional AI-2 binding proteins but not in the non-AI-2-binding orthologs. Together, these results strongly support our ability to identify functional LsrB-type AI-2 receptors, an important step in investigations of this interspecies signal.
| S-EPMC2772480 | biostudies-literature
Project description:The autoinducer-2 (AI-2) quorum-sensing system has been linked to diverse phenotypes and regulatory changes in pathogenic bacteria. In the present study, we performed a molecular and biochemical characterization of the AI-2 system in Yersinia pestis, the causative agent of plague. In strain CO92, the AI-2 signal is produced in a luxS-dependent manner, reaching maximal levels of 2.5 ?M in the late logarithmic growth phase, and both wild-type and pigmentation (pgm) mutant strains made equivalent levels of AI-2. Strain CO92 possesses a chromosomal lsr locus encoding factors involved in the binding and import of AI-2, and confirming this assignment, an lsr deletion mutant increased extracellular pools of AI-2. To assess the functional role of AI-2 sensing in Y. pestis, microarray studies were conducted by comparing ?pgm strain R88 to a ?pgm ?luxS mutant or a quorum-sensing-null ?pgm ?ypeIR ?yspIR ?luxS mutant at 37°C. Our data suggest that AI-2 quorum sensing is associated with metabolic activities and oxidative stress genes that may help Y. pestis survive at the host temperature. This was confirmed by observing that the luxS mutant was more sensitive to killing by hydrogen peroxide, suggesting a potential requirement for AI-2 in evasion of oxidative damage. We also show that a large number of membrane protein genes are controlled by LuxS, suggesting a role for quorum sensing in membrane modeling. Altogether, this study provides the first global analysis of AI-2 signaling in Y. pestis and identifies potential roles for the system in controlling genes important to disease.
| S-EPMC3811820 | biostudies-literature
Project description:BackgroundQuorum sensing is a mechanism of cell to cell communication that requires the production and detection of signaling molecules called autoinducers. Although mesophilic bacteria is known to utilize this for synchronization of physiological processes such as bioluminescence, virulence, biofilm formation, motility and cell competency through signaling molecules (acyl homoserine lactones, AI-1; oligopeptides, peptide based system and furanosyl borate diester, AI-2), the phenomenon of quorum sensing in thermophiles is largely unknown.ResultsIn this study, proteomes of 106 thermophilic eubacteria and 21 thermophilic archaea have been investigated for the above three major quorum sensing systems to find the existence of quorum sensing in these thermophiles as there are evidences for the formation of biofilms in hot environments. Our investigation demonstrated that AI-1 system is absent in thermophiles. Further, complete peptide based two component systems for quorum sensing was also not found in any thermophile however the traces for the presence of response regulators for peptide based system were found in some of them. BLASTp search using LuxS (AI-2 synthase) protein sequence of Escherichia coli str. K-12 substr. MG1655 and autoinducer-2 receptors (LuxP of Vibrio harveyi, LsrB of E. coli str. K-12 substr. MG1655 and RbsB of Aggregatibacter actinomycetemcomitans) as queries revealed that 17 thermophilic bacteria from phyla Deinococcus- Thermus and Firmicutes possess complete AI-2 system (LuxS and LsrB and/or RbsB). Out of 106 thermophilic eubacteria 18 from phyla Deinococcus- Thermus, Proteobacteria and Firmicutes have only LuxS that might function as AI-2 synthesizing protein whereas, 16 are having only LsrB and/or RbsB which may function as AI-2 receptor in biofilms.ConclusionsWe anticipate that thermophilic bacteria may use elements of LsrB and RbsB operon for AI-2 signal transduction and they may use quorum sensing for purposes like biofilm formation. Nevertheless, thermophiles in which no known quorum sensing system was found may use some unknown mechanisms as the mode of communication. Further information regarding quorum sensing will be explored to develop strategies to disrupt the biofilms of thermophiles.
| S-EPMC6022435 | biostudies-literature
Project description:Xenotropic/polytropic mouse leukemia viruses (X/P-MLVs) use the XPR1 gammaretrovirus receptor for entry. X/P-MLV host range is defined by usage of naturally occurring restrictive XPR1 receptors, and is governed by polymorphisms in the virus envelope glycoprotein and in XPR1. Here, we examined receptors of four mammalian species permissive to all X/P-MLVs (Mus dunni, human, rabbit, mink). Interference assays showed the four to be functionally distinct. Preinfection with X-MLVs consistently blocked all nine XPR1-dependent viruses, while preinfection with P-MLVs and wild mouse X/P-MLVs produced distinctive interference patterns in the four cells. These patterns indicate shared usage of independent, but not always fully functional, receptor sites. XPR1 sequence comparisons identified candidate sites in receptor-determining regions that correlate with some interference patterns. The evolutionary record suggests that the X/P-MLV tropism variants evolved to adapt to host receptor polymorphisms, to circumvent blocks by competing viruses or to avoid host-encoded envelope glycoproteins acquired for defense.
| S-EPMC5026577 | biostudies-literature
Project description:Host-microbial symbioses are vital to health; nonetheless, little is known about the role crosskingdom signaling plays in these relationships. In a process called quorum sensing, bacteria communicate with one another using extracellular signal molecules called autoinducers. One autoinducer, AI-2, is proposed to promote interspecies bacterial communication, including in the mammalian gut. We show that mammalian epithelia produce an AI-2 mimic activity in response to bacteria or tight-junction disruption. This AI-2 mimic is detected by the bacterial AI-2 receptor, LuxP/LsrB, and can activate quorum-sensing-controlled gene expression, including in the enteric pathogen Salmonella typhimurium. AI-2 mimic activity is induced when epithelia are directly or indirectly exposed to bacteria, suggesting that a secreted bacterial component(s) stimulates its production. Mutagenesis revealed genes required for bacteria to both detect and stimulate production of the AI-2 mimic. These findings uncover a potential role for the mammalian AI-2 mimic in fostering crosskingdom signaling and host-bacterial symbioses.
| S-EPMC4869860 | biostudies-literature