The Mechanisms and Applications of Quorum Sensing(QS) and Quorum Quenching(QQ)

Quorum sensing(QS)is a regulatory system that regulates the behavior of microbial populations by sensing the concentration of signal molecules that are spontaneously produced and released by bacteria.The strategy of blocking the QS system and inhibiting the production of virulence factors is termed as quorum quenching(QQ).This strategy attenuates virulence without killing the pathogens,thereby weakening the selective pressure on pathogens and postponing the evolution of QQ-mediated drug resistance.In recent years,there have been significant theoretical and practical developments in the field of QS and QQ.In particular,with the development and utilization of marine resources,more and more marine microbial species have been found to be regulated by these two mechanisms,further promoting the research progress of QS and QQ.In this review,we described the diversity of QS signals and QS-related regulatory systems,and then introduced mechanisms related to QS interference,with particular emphasis on the description of natural QQ enzymes and chemicals acting as QS inhibitors.Finally,the exploitation of quorum sensing quenchers and the practical application of QQ were introduced,while some QQ strategies were proposed as promising tools in different fields such as medicine,aquaculture,agriculture and biological pollution prevention areas.

Metabolic activities of marine ammonia-oxidizing archaea orchestrated by quorum sensing

Ammonia-oxidizing archaea(AOA)play crucial roles in marine carbon and nitrogen cycles by fixing inorganic carbon and performing the initial step of nitrification.Evaluation of carbon and nitrogen metabolism popularly relies on functional genes such as amoA and accA.Increasing studies suggest that quorum sensing(QS)mainly studied in biofilms for bacteria may serve as a universal communication and regulatory mechanism among prokaryotes;however,this has yet to be demonstrated in marine planktonic archaea.To bridge this knowledge gap,we employed a combination of metabolic activity markers(amoA,accA,and grs)to elucidate the regulation of AOA-mediated nitrogen,carbon processes,and their interactions with the sur-rounding heterotrophic population.Through co-transcription investigations linking metabolic markers to potential key QS genes,we discovered that QS molecules could regulate AOA's carbon,nitrogen,and lipid metabolisms under different conditions.Interestingly,specific AOA ecotypes showed a preference for employing distinct QS systems and a distinct QS circuit involving a typical population.Overall,our data demonstrate that Qs orchestrates nitrogen and carbon metabolism,including the exchange of organic metabolites between AOA and surrounding heterotrophic bacteria,which has been pre-viously overlooked in marine AOA research.

Discovery of β-nitrostyrene derivatives as potential quorum sensing inhibitors for biofilm inhibition and antivirulence factor therapeutics against Serratia marcescens

Quorum sensing(Qs)inhibition has emerged as a promising target for directed drug design,providing an appealing strategy for developing antimicrobials,particularly against infections caused by drug-resistant pathogens.In this study,we designed and synthesized a total of 33β-nitrostyrene derivatives using 1-nitro-2-phenylethane(NPe)as the lead compound,to target the facultative anaerobic bacterial pathogen Serratia marcescens.The QS-inhibitory effects of these compounds were evaluated using S.marcescens NJ01 and the reporter strain Chromobacterium violaceum CV026.Among the 33 newβ-nitrostyrene derivatives,(E)-1-methyl-4-(2-nitrovinyl)benzene(m-NPe,compound 28)was proven to be a potent inhibitor that reduced biofilm formation of S.marcescens NJ01 by 79%.Scanning electron microscopy(SEM)and confocal laser scanning microscopy(CLSM)results revealed that treatment with m-NPe(50μg/ml)not only enhanced the susceptibility of the formed biofilms but also disrupted the architecture of biofilms by 84%.m-NPe(50μg/ml)decreased virulence factors in S.marcescens NJ01,reducing the activity of protease,prodigiosin,and extracellular polysaccharide(EPs)by 36%,72%,and 52%,respectively.In S.marcescens 4547,the activities of hemolysin and EPs were reduced by 28%and 40%,respectively,outperforming the positive control,vanillic acid(VAN).The study also found that the expression levels of QS-and biofilm-related genes(flhD,fimA,fimC,sodB,bsmB,pigA,pigC,and shlA)were downregulated by 1.21-to 2.32-fold.Molecular dynamics analysis showed that m-NPe could bind stably to SmaR,Rhll,RhiR,LasR,and CviR proteins in a 0.1 M sodium chloride solution.Importantly,a microscale thermophoresis(MST)test revealed that SmaR could be a target protein for the screening of a quorum sensing inhibitor(QSl)against S.marcescens.Overall,this study highlights the efficacy of m-NPe in suppressing the virulence factors of S.marcescens,identifying it as a new potential Qsl and antibiofilm agent capable of restoring or improving antimicrobial drug sensitivity.

细菌的群体行为调控机制-Quorum sensing

群体效应 (Quorumsensing)是近来日益受到广泛关注的一种细菌群体行为调控机制 ,很多细菌有这种能力 ,即分泌一种或多种自诱导剂 (Autoinducer) ,细菌通过感应这些自诱导剂来判断菌群密度和周围环境变化 ,当菌群数达到一定的阀值 (quorum ,菌落或集落数 )后 ,启动相应一系列基因的调节表达 ,以调节菌体的群体行为。不同类型的细菌具有不同的群体效应调节系统 ,很多细菌分泌同一种诱导剂 ,以此调控不同种类细菌间的作用行为。群体效应系统在自诱导剂与受体之间存在专一性 ,同时又在调节基因和信号传递系统中体现出多样性和复杂性。由于不少人或植物的病原菌的致病机制等受群体效应的调控 。

细菌感染性疾病中的对立统一规律与Quorum Sensing系统

引起人类细菌性感染的病原菌可以分为条件致病菌和非条件致病菌,不同性质的细菌引起的感染决定了感染矛盾的特殊性,对于不同质的矛盾,只有用不同质的方法才能解决。抗生素的发明和使用为人类控制感染性疾病的同时,这种单纯的“对抗”的解决方法也引出了一些新的矛盾。因此,细菌感染矛盾的特殊性决定我们不能采用千篇一律的“对抗斗争”形式,而必须寻求一种特殊的解决方式。对QS系统的研究发现在细菌表现致病性过程中发挥重要作用,通过QS系统减弱细菌的致病性而不杀死细菌的“抗致病性药物”来治疗感染成为一种新的抗感染思路,这种“抗致病性”概念使我们抗感染的态度从与细菌“对抗”转变为“共生”,因而QS系统可以为这种特殊矛盾提供一个合理的解决方式。

假单胞菌Quorum sensing调控体系

群体感应(Quorum sensing,QS)是近来受到广泛关注的一种细菌群体行为调控机制,通过感应一些信号分子如酰基高丝氨酸环内酯(acyl-homoserine lactone,AHL)来判断菌群密度和周围环境变化,假单胞菌中同样也有AHL信号分子,当信号达到一定的浓度阈值时,能启动菌体中相关基因的表达来适应环境中的变化,从而调节菌体的群体行为(如致病性及群体生长调节)。众多报道说明了假单胞菌的群体感应调节系统是由一些全面的调节子所调控的。本文系统介绍了假单胞菌群体感应调控系统,并分析假单胞菌在该系统中复杂的应答反应。

Essential oils of Origanum compactum increase membrane permeability,disturb cell membrane integrity,and suppress quorum-sensing phenotype in bacteria

The aim of this study was to investigate antibacterial activity of Origanum compactum essential oils collected at three phenological stages on Escherichia coli and Bacillus subtilis. The antibacterial activity was evaluated using the agar-well diffusion assay. The MIC and MBC values were determined using the micro-dilution assay. The investigation of the antibacterial action was carried out by the evaluation of the effect of O. compactum essential oils on the antibacterial kinetic growth, the integrity of cell membrane and permeability of the cell membrane. The anti-quorum sensing activity was tested by the inhibition of the biofilm formation. The findings of this study showed that O. compactum essential oil has potent antibacterial activities against E. coli and B. subtilis. The lowest inhibition value against B. subtilis was obtained with O. compactum essential oil at the post-flowering stage (MIC=MBC=0.0312%(v/v)). The antibacterial mechanisms of O. compactum essential oils are related to the disturbing of the cell membrane integrity and the increasing of the membrane permeability, which leads to the leakage of genetic materials (DNA and RNA). Moreover, O. compactum essential oils inhibited the formation of the biofilms, a phenotype that has been known to be quorum sensing regulated.

嗜水气单胞菌AH-1 quorum sensing负调控Ⅲ型分泌系统的表达

通过构建嗜水气单胞菌AH-1 Quorum Sensing(QS)2个关键调节基因ahyI,ahyR的突变菌株,来系统分析嗜水气单胞菌AH-1Ⅲ型分泌系统基因,揭示它们由QS系统调控.在ahyI突变菌中,TTSS分泌效应因子(effector)aexT量显著提高.通过构建LacZ-TTSS基因启动子融合表达,进一步表明QS系统负调控编码TTSS组分的基因.

LsrR-binding site recognition and regulatory characteristics in Escherichia coli AI-2 quorum sensing

In quorum sensing （QS） process, bacteria regulate gene expression by utilizing small signaling molecules called autoinducers in response to a variety of environmental cues. Autoinducer 2 （AI-2）, a QS signaling molecule proposed to be involved in interspecies communication, is produced by many species of gram-negative and gram-positive bacteria. In Escherichia coil and Salmonella typhimurium, the extracellular AI-2 is imported into the cell by a transporter encoded by the lsr operon. Upstream of the lsr operon, there is a divergently transcribed gene encoding LsrR, which was reported previously to repress the transcription of the lsr operon and itself. Here, we have demonstrated for the first time that LsrR represses the transcription of the lsr operon and itself by directly binding to their promoters using gel shift and DNase I footprinting assays. The β-galactosidase reporter assays further suggest that two motifs in both the lsrR and lsrA promoter regions are crucial for the LsrR binding. Furthermore, in agreement with the conclusion that phosphorylated AI-2 can relieve the repression of LsrR in previous studies, our data show that phospho- AI-2 renders LsrR unable to bind to its own promoter in vitro.

Role of quorum sensing in bacterial infections

Quorum sensing(QS) is cell communication that is widely used by bacterial pathogens to coordinate the expression of several collective traits, including the production of multiple virulence factors, biofilm formation, and swarming motility once a population threshold is reached. Several lines of evidence indicate that QS enhances virulence of bacterial pathogens in animal models as well as in human infections; however, its relative importance for bacterial pathogenesis is still incomplete. In this review, we discuss the present evidence from in vitro and in vivo experiments in animal models, as well as from clinical studies, that link QS systems with human infections. We focus on two major QS bacterial models, the opportunistic Gram negative bacteria Pseudomonas aeruginosa and the Gram positive Staphylococcus aureus, which are also two of the main agents responsible of nosocomial and wound infections. In addition, QS communication systems in other bacterial, eukaryotic pathogens, and even immune and cancer cells are also reviewed, and finally, the new approaches proposed to combat bacterial infections by the attenuation of their QS communication systems and virulence are also discussed.

Medicinal plant products targeting quorum sensing for combating bacterial infections

Traditional treatment of infectious diseases is based on compounds that aim to kill or inhibit bacterial growth. The bacterial resistance against antibiotics is a serious issue for public health. Today, new therapeutic targets other than the bacterial wall were deciphered. Quorum sensing or bacterial pheromones are molecules called auto-inducer secreted by bacteria to regulate some functions such as antibiotic resistance and biofilms formation. This therapeutic target is well-studied worldwide, nevertheless the scientific data are not updated and only recent researches started to look into its potential as a target to fight against infectious diseases. A major concern with this approach is the frequently observed development of resistance to antimicrobial compounds. Therefore, this paper aims to provide a current overview of the quorum sensing system in bacteria by revealing their implication in biofilms formation and the development of antibiotic resistance, and an update on their importance as a potential target for natural substances.

Inhibition of quorum sensing in Chromobacterium violaceum by Syzygium cumini L.and Pimenta dioica L.

Objective:To investigated into the anti-quorum sensing(QS)activity of Syzygium cumini L.(S.cumini)and Pimenta dioica L.(P.dioica)using Chromobacterium violaceum(C.violaceum)strains.Methods:In this study,anti-QS activity of ethanol extract of Syzygium cumini L.and Pimenta dioica L.were screened using C.violaceum CV026 biosensor bioassay.By bioassay guided fractionation of 5.cumini and P.dioica,ethyl acetate fraction(EAF)with strong anti-QS activity was separated.Inhibition of QS regulated violacein production in C.violaceum ATCC12472 by EAF was assessed at different concentrations.The effect of EAF on the synthesis of autoinducer like N-acyl homoserine lactone(AHL)was studied in C.violaceum ATCC31532 using its mutant C.violaceum CV026 by standard methods.Results:EAF inhibited violacein production in C.violaceum ATCC12472 in a concentration dependent manner without significant reduction in bacterial growth.Complete inhibition of violacein production was evidenced in 0.75-1.0 mg/mL concentration of EAF without inhibiting the synthesis of the AHL.TLC biosensor overlay profile of EAF revealed two translucent spots in 5.cumini and P.dioica that inhibited C_6-AHL mediated violacein production in C.violaceum CV026.Conclusions:This study indicates the anti-QS activity of the tested medicinal plants against C.violaceum.

Screening strategies for quorum sensing inhibitors in combating bacterial infections

Interference with quorum sensing(QS)represents an antivirulence strategy with a significant promise for the treatment of bacterial infections and a new approach to restoring antibiotic tolerance.Over the past two decades,a novel series of studies have reported that quorum quenching approaches and the discovery of quorum sensing inhibitors(QSIs)have a strong impact on the discovery of anti-infective drugs against various types of bacteria.The discovery of QSI was demonstrated to be an appropriate strategy to expand the anti-infective therapeutic approaches to complement classical antibiotics and antimicrobial agents.For the discovery of QSIs,diverse approaches exist and develop in-step with the scale of screening as well as specific QS systems.This review highlights the latest findings in strategies and methodologies for QSI screening,involving activity-based screening with bioassays,chemical methods to seek bacterial QS pathways for QSI discovery,virtual screening for QSI screening,and other potential tools for interpreting QS signaling,which are innovative routes for future efforts to discover additional QSIs to combat bacterial infections.

An EAL domain protein and cyclic AMP contribute to the interaction between the two quorum sensing systems in Escherichia coli

Quorum sensing （QS） is a bacterial cell-cell communication process by which bacteria communicate using extracellular signals called autoinducers. Two QS systems have been identified in Escherichia coli K-12, including an intact QS system 2 that is stimulated by the cyclic AMP （cAMP）-cAMP receptor protein （CRP） complex and a partial QS system 1 that consists of SdiA （suppressor of cell division inhibitor） responding to signals generated by other microbial species. The relationship between QS system 1 and system 2 in E. coli, however, remains obscure. Here, we show that an EAL domain protein, encoded by ydiV, and cAMP are involved in the interaction between the two QS systems in E. coli. Expression of sdiA and ydiV is inhibited by glucose. SdiA binds to the ydiV promoter region in a dose-dependent, but nonspecific, manner; extracellular autoinducer 1 from other species stimulates ydiV expression in an sdiA-depen- dent manner. Furthermore, we discovered that the double sdiA-ydiV mutation, but not the single mutation, causes a 2-fold decrease in intracellular cAMP concentration that leads to the inhibition of QS system 2. These results indicate that signaling pathways that respond to important environmental cues, such as autoinducers and glucose, are linked together for their control in E. coli.

Initial detection of the quorum sensing autoinducer activity in the rumen of goats in vivo and in vitro

Quorum sensing（QS） is a type of microbe-microbe communication system that is widespread among the microbial world, particularly among microorganisms that are symbiotic with plants and animals. Thereby, the cell-cell signalling is likely to occur in an anaerobic rumen environment, which is a complex microbial ecosystem. In this study, using six ruminally fistulated Liuyang black goats as experimental animals, we aimed to detect the activity of quorum sensing autoinducers（AI） both in vivo and in vitro and to clone the lux S gene that encoded autoinducer-2（AI-2） synthase of microbial samples that were collected from the rumen of goats. Neutral detergent fiber（NDF） and soluble starch were the two types of substrates that were used for in vitro fermentation. The fermented fluid samples were collected at 0, 2, 4, 6, 8, 12, 24, 36, and 48 h of incubation. The acyl-homoserine lactones（AHLs） activity was determined using gas chromatography-mass spectrometer（GC-MS） analysis. However, none of the rumen fluid extracts that were collected from the goat rumen showed the same or similar fragmentation pattern to AHLs standards. Meanwhile, the AI-2 activity, assayed using a Vibrio harveyi BB170 bioassay, was negative in all samples that were collected from the goat rumen and from in vitro fermentation fluids. Our results indicated that the activities of AHLs and AI-2 were not detected in the ruminal contents from six goats and in ruminal fluids obtained from in vitro fermentation at different sampling time-points. However, the homologues of lux S in Prevotella ruminicola were cloned from in vivo and in vitro ruminal fluids. We concluded that AHLs and AI-2 could not be detected in in vivo and in vitro ruminal fluids of goats using the current detection techniques under current dietary conditions. However, the microbes that inhabited the goat rumen had the potential ability to secrete AI-2 signaling molecules and to communicate with each other via AI-2-mediated QS because of the presence of lux S.

Anti-quorum sensing and anti-biofilm formation activities of plant extracts from South Korea

Objective: To investigate anti-quorum sensing(anti-QS) and anti-biofilm formation(antiBF) activities of the ethanol extracts of 388 plants. Methods: The anti-QS activity of the plant extracts was evaluated by disc-diffusion assays using the bio-reporter strain, Chromobacterium violaceum CV017. Pseudomonas aeruginosa PAO1, Yersinia enterocolitica ATCC 9610, and Agrobacterium tumefaciens C58, which possess QS systems, were used to evaluate the antiBF activity of the plant extracts. Results: Among 388 plant extracts, the Cornus controversa(C. controversa) and Cynanchum wilfordii extracts exhibited the strongest anti-QS activity. The C. controversa extract exhibited anti-BF activity against Pseudomonas aeruginosa, Yersinia enterocolitica and Agrobacterium tumefaciens, whereas the Cynanchum wilfordii extract exhibited no anti-BF activity against Pseudomonas aeruginosa. In addition, the C. controversa extract suppressed soft rot of cabbage. Conclusions: The C. controversa extract inhibits bacterial QS and BF, and is capable of controlling soft rot. Therefore, this extract has potential for the prevention and treatment of bacterial infections and for the development of alternatives to antibiotics.

Gossip in the gut: Quorum sensing, a new player in the hostmicrobiota interactions

Bacteria are known to communicate with each other and regulate their activities in social networks by secreting and sensing signaling molecules called autoinducers,a process known as quorum sensing(QS).This is a growing area of research in which we are expanding our understanding of how bacteria collectively modify their behavior but are also involved in the crosstalk between the host and gut microbiome.This is particularly relevant in the case of pathologies associated with dysbiosis or disorders of the intestinal ecosystem.This review will examine the different QS systems and the evidence for their presence in the intestinal ecosystem.We will also provide clues on the role of QS molecules that may exert,directly or indirectly through their bacterial gossip,an influence on intestinal epithelial barrier function,intestinal inflammation,and intestinal carcinogenesis.This review aims to provide evidence on the role of QS molecules in gut physiology and the potential shared by this new player.Better understanding the impact of intestinal bacterial social networks and ultimately developing new therapeutic strategies to control intestinal disorders remains a challenge that needs to be addressed in the future.

Quorum-Sensing of Bacteria and Its Application

Quorum sensing, or auto induction, as a cell density dependent signaling mechanism in many microorganisms, is trig- gered via auto inducers which passively diffuse across the bacterial envelope and therefore intracellulaly accumulate only at higher bacterial densities to regulate specialized processes such as genetic competence, bioluminescence, virulence and sporulation. N-acyl homoserine lactones are the most common type of signal molecules. Aquaculture is one of the fastest-growing food-producing indus- tries, but disease outbreaks caused by pathogenic bacteria are a significant constraint on the development of the sector worldwide. Many of these pathogens have been found to be controlled by their quorum sensing systems. As there is relevance between the pathogenic bacteria＇s virulence factor expression and their auto inducers, quorum quenching is a new effective anti-infective strategy to control infections caused by bacterial pathogens in aquaculture. The techniques used to do this mainly include the following： （1） the inhibition of signal molecule biosynthesis, （2） blocking signal transduction, and （3） chemical inactivation and biodegradation of signal molecules. To provide a basis for finding alternative means of controlling aquatic diseases by quorum quenching instead of treatment by antibiotics and disinfectants, we will discuss the examination, purification and identification of auto inducers in this paper.

Monooxygenase Gene from Acinetobacter sp. C42 Inactivates the Acyl Homoserine Lactone Quorum Sensing Signal

[ Objective] This study aimed to investigate the function of aliD gene in the inactivation of AHLs. [ Method ] A bacterial isolate, Acinetobacter sp. CA2 from soil, is capable of inactivation of AHLs. A gene designed as aliD, which is responsible for AHL-quenching activity and exhibits high similarity with Mo- nooxygenase genes, was cloned from the genomic library of Acinetobacter sp. CA2. [ Result ] The aliD gene in-frame deletion mutant, CA2 AliD, impaired its AHLs inactivating function when mixed with N-（3-oxooctanoyl） -L-homosefine lactone （30C8-HSL）. Expression of AliD in plant pathogenic bacterium Pectobacterium ca- rotovorum subsp, carotovorum Z3-3 significantly reduced the AHLs production and the extracellular pectolytic enzyme activities, and attenuated soft rot disease symptoms on the plants tested, including potato, Chinese cabbage, radish and cabbage. [ Conclusion ] Our study suggests that the aliD gene complemented strain CA2-AliD showes a similar AHLs inactivating function.

Dynamics and Mechanism of A Quorum Sensing Network Regulated by Small RNAs in Vibrio Harveyi

Bacterial quorum sensing （QS） has attracted much interests and it is an important process of cell communication. Recently, Bassler et al. studied the phenomena of QS regulated by small RNAs and the experimental data showed that smafl RNAs played important role in the QS of Vibrio harveyi and it can permit the fine-tuning of gene regulation and mmntenance of homeostasis. According to Michaelis-Menten kinetics and mass action law in this paper, we construct a mathematical model to investigate the mechanism induced QS by coexist of small RNA and signal molecular （AI） and show that there are periodic oscillation when the time delay and Hill coefficient exceed a critical value and the periodic oscillation produces the change of concentration and induces QS. These results are fit to the experimental results. In the meanwhile, we also get some theoretical value of Hopf Bifurcation on time deday. In addition, we also find this network is robust against noise.