Quorum Sensing Signaling Systems Research Articles

Cinnamoyl lipids as novel signaling molecules modulate the physiological metabolism of cross-phylum microorganisms

Signaling systems of microorganisms are responsible for regulating the physiological and metabolic processes and also play vital roles in the communications of cells. Identifying signaling molecules mediating the cross-talks is challenging yet highly desirable for comprehending the microbial interactions. Here, we demonstrate that a pathogenic Gram-negative Chromobacterium violaceum exerts significant influence on the morphological differentiation and secondary metabolism of Gram-positive Streptomyces. The physiological metabolisms are directly modulated by three novel cinnamoyl lipids (CVCL1, 2, and 3) from C. violaceum CV12472, whose biosynthesis is under the control of N-acylhomoserine lactone signaling system. Furthermore, a receptor of CVCLs in Streptomyces ansochromogenes 7100 is determined to be SabR1, the cognate receptor of γ-butenolide signaling molecules. This study reveals an unprecedented mode of microbial interactions, and the quorum sensing signaling systems in these two groups of bacteria can be bridged via CVCLs, suggesting that CVCLs can modulate the physiological metabolism of cross-phylum microorganisms.

Study on molecular epidemiology of carbapenem resistant Pseudomonas aeruginosa and related genes of quorum sensing signal system

This study aims to investigate the drug resistance, regulation mechanism of quorum sensing system, expression of related virulence genes, and epidemiological characteristics of carbapenem-resistant Pseudomonas aeruginosa (CRPA).In this study, Polymerase chain reaction amplification was performed to evaluate carbapenemase genes, OprD2 gene, quorum sensing system, and related virulence genes. Bacterial genotypes were analyzed using multilocus sequence typing and evolutionary analysis was conducted based on the goeBURST algorithm. The results demonstrated that a total of 47 CRPA strains were collected in this study, primarily from respiratory specimens in the ICU. Drug sensitivity results showed that the resistance rates of the 47 CRPA strains were highest for imipenem (97.87 %). The loss of OprD2 may be the main factor contributing to carbapenem resistance in our hospital's CRPA strains.All isolates tested positive for the quorum sensing system genes lasI and rhlI/R, and the virulence gene lasB was detected in all isolates, while the algD gene was detected in 19.15 % of the isolates. Among the 47 strains, 6 were untypeable, and the 41 strains with 28 different sequence types were clustered into three clonal complexes (BG1, BG2, and BG3).In conclusion, the CRPA isolates from our hospital exhibit high genetic diversity, with the deletion of the OprD2 gene possibly being the primary determinant of carbapenem resistance in Pseudomonas aeruginosa.Moreover, Las and RhI systems play a key role in quorum sensing signal system. Further research and development of drugs targeting quorum sensing signaling system may provide valuable guidance for the treatment of CRPA.

N-acyl homoserine lactone cell-cell diffusible signalling in the Ralstonia solanacearum species complex.

Ralstonia solanacearum species complex (RSSC) includes soilborne bacterial plant pathogens with worldwide distribution and wide host ranges. Virulence factors are regulated via four hierarchically organized cell-cell contact independent quorum-sensing (QS) signalling systems: the Phc, which uses as signals (R)-methyl 3-hydroxypalmitate [(R)-3-OH PAME] or (R)-methyl 3-hydroxymyristate [(R)-3-OH MAME], the N-acyl homoserine lactone (AHL)-dependent RasI/R and SolI/R systems, and the recently identified anthranilic acid-dependent system. The unique Phc QS system has been extensively studied; however, the role of the two AHL QS systems has only recently been addressed. In this microreview, we present and discuss current data of the SolI/R and RasI/R QS systems in the RSSC. We also present the distribution and frequency of these AHL QS systems in the RSSC, discuss possible ecological roles and evolutive implications. The complex QS hierarchical networks emphasizes the crucial role of cell-cell signalling in the virulence of the RSSC.

RsaL is a self-regulatory switch that controls alternative biosynthesis of two AHL-type quorum sensing signals in Pseudomonas aeruginosa PA1201.

Pseudomonas aeruginosa is a ubiquitous and metabolically versatile microorganism naturally found in soil and water. It is also an opportunistic pathogen in plants, insects, animals, and humans. In response to increasing cell density, P. aeruginosa uses two acyl-homoserine lactone (AHL) quorum-sensing (QS) signals (i.e.,N-3-oxo-dodecanoyl homoserine lactone [3-oxo-C12-HSL] and N-butanoyl-homoserine lactone [C4-HSL]), which regulate the expression of hundreds of genes. However, how the biosynthesis of these two QS signals is coordinated remains unknown. We studied the regulation of these two QS signals in the rhizosphere strain PA1201. PA1201 sequentially produced 3-oxo-C12-HSL and C4-HSL at the early and late growth stages, respectively. The highest 3-oxo-C12-HSL-dependent elastase activity was observed at the early stage, while the highest C4-HSL-dependent rhamnolipid production was observed at the late stage. The atypical regulator RsaL played a pivotal role in coordinating 3-oxo-C12-HSL and C4-HSL biosynthesis and QS-associated virulence. RsaL repressed lasI transcription by binding the -10 and -35 boxes of the lasI promoter. In contrast, RsaL activated rhlI transcription by binding the region encoding the 5'-untranslated region of the rhlI mRNA. Further, RsaL repressed its own expression by binding a nucleotide motif located in the -35 box of the rsaL promoter. Thus, RsaL acts as a molecular switch that coordinates the sequential biosynthesis of AHL QS signals and differential virulence in PA1201. Finally, C4-HSL activation by RsaL was independent of the Las and Pseudomonas quinolone signal (PQS) QS signaling systems. Therefore, we propose a new model of the QS regulatory network in PA1201, in which RsaL represents a superior player acting at the top of the hierarchy.

An Insilico Study of Quinic Acid Derivatives as Inhibitors of Com A, The Quorum Sensing Protein of Streptococcus Mutans Responsible for The Pathogenesis in Dental Caries

Dental caries is considered to be one of the important infectious diseases throughout the world. It was recognized that the Streptococcus mutans, plays an important role in cariogenesis. The oral streptococci in biofilms may communicate by a quorum-sensing CSP signalling system. The products of at least six genes, comAB, comX, and comCDE, are involved in CSP signalling. It has been proved that loss of Com A attenuates the formation of biofilm. In the present study quinic acid derivatives have been developed insilico as the inhibitors of Com A and a molecular docking study is performed to find its efficiency as inhibitors. The three-dimensional structure of Com A was retrieved from RCSB- PDB database. The possible binding sites of Com A were searched using binding site prediction 3DLIGANDSITE. The structure of quinic acid was obtained from ZINC database. A total of 100 ligands were generated with the help of software ACD chemsketch. Rapid virtual screenings of these compounds were performed in the docking tool iGEMDOCK v2.0. Based on the binding energy a total of five ligands were selected for the further study. The selected five ligands were then analyzed for drug- relevant properties based on “Lipinski’s rule of five” and other drug like properties. The docking of five ligands was performed using AutoDock 4.0 software. From the present study, it has been found that (1R)-1, 3, 4- trihydroxy-5-methylcyclohexane carboxylic acid, which is a novel compound, a derivative of quinic acid, can act has an inhibitor for the Com A.

Exploration of Chemical Diversity in Intercellular Quorum Sensing Signalling Systems in Prokaryotes.

Quorum sensing (QS) serves as a vital means of intercellular signalling in a variety of prokaryotes, which enables single cells to act in multicellular configurations. The potential to control community-wide responses has also sparked numerous recent biotechnological innovations. However, our capacity to utilize intercellular communication is hindered due to a scarcity of complementary signalling systems and a restricted comprehension of interconnections between these systems caused by variations in their dynamic range. In this study, we utilize uniform manifold approximation and projection and extended-connectivity fingerprints to explore the available chemical space of QS signalling molecules. We investigate and experimentally characterize a set of closely related QS signalling ligands, consisting of N-acyl homoserine lactones and the aryl homoserine lactone p-coumaroyl, as well as a set of more widely diverging QS ligands, consisting of photopyrones, dialkylresorcinols, 3,5-dimethylpyrazin-2-ol and autoinducer-2, and define their performance. We report on a set of six signal- and promoter-orthogonal intercellular QS signalling systems, significantly expanding the toolkit for engineering community-wide behaviour. Furthermore, we demonstrate that ligand diversity can serve as a statistically significant tool to predict much more complicated ligand-receptor interactions. This approach highlights the potential of dimensionality reduction to explore chemical diversity in microbial dynamics.

Exploration of Chemical Diversity in Intercellular Quorum Sensing Signalling Systems in Prokaryotes

AbstractQuorum sensing (QS) serves as a vital means of intercellular signalling in a variety of prokaryotes, which enables single cells to act in multicellular configurations. The potential to control community‐wide responses has also sparked numerous recent biotechnological innovations. However, our capacity to utilize intercellular communication is hindered due to a scarcity of complementary signalling systems and a restricted comprehension of interconnections between these systems caused by variations in their dynamic range. In this study, we utilize uniform manifold approximation and projection and extended‐connectivity fingerprints to explore the available chemical space of QS signalling molecules. We investigate and experimentally characterize a set of closely related QS signalling ligands, consisting of N‐acyl homoserine lactones and the aryl homoserine lactone p‐coumaroyl, as well as a set of more widely diverging QS ligands, consisting of photopyrones, dialkylresorcinols, 3,5‐dimethylpyrazin‐2‐ol and autoinducer‐2, and define their performance. We report on a set of six signal‐ and promoter‐orthogonal intercellular QS signalling systems, significantly expanding the toolkit for engineering community‐wide behaviour. Furthermore, we demonstrate that ligand diversity can serve as a statistically significant tool to predict much more complicated ligand‐receptor interactions. This approach highlights the potential of dimensionality reduction to explore chemical diversity in microbial dynamics.

Modeling downstream impact of a quorum sensing system of Pseudomonas aeruginosa in colony spreading

A single bacterial colony typically consists of two or more individual cells. To further growth, the cells within the colony need to coordinate through Quorum Sensing (QS), which serves as a communication mechanism between cells. The Quorum Sensing signalling system in Pseudomonas aeruginosa is known to involve multiple control components, notably the las and rhl systems. The las system controls the rhl system in a hierarchical signalling cascade, and the rhl system regulates certain gene expressions, including the rhlA and rhlB genes. Transcription of rhlA and rhlB results in the production of the enzyme rhamnosyltransferase, which leads to the biosurfactant production identified as rhamnolipids. In this paper, we investigate how the las system controls the rhl system to influence rhamnolipids production. We illustrate how the pulsed production of signal molecules in the las system affects the rhl system, leading to an increase in rhamnolipids concentration. Rhamnolipids play a crucial role in bacterial spreading. We employ a simple symmetric diffusion model to simulate colony spreading and demonstrate how bacteria spread from the centre of the colony. Our findings shed light on the interaction between the las and rhl systems, which may enable cells to trigger rhamnolipids production at the edge of the bacterial colony.

Inhibition of Pseudomonas aeruginosa quorum sensing by methyl gallate from Mangifera indica

Antipathogenic drugs are a potential source of therapeutics, particularly following the emergence of multiple drug-resistant pathogenic microorganisms in the last decade. The inhibition of quorum sensing (QS) is an advanced antipathogenic approach for suppression of bacterial virulence and dissemination. This study aimed to investigate the inhibitory effect of some Egyptian medicinal plants on the QS signaling system of Pseudomonas aeruginosa. Among the tested plants, Mangifera indica exhibited the highest quorum sensing inhibition (QSI) activity against Chromobacterium violaceum ATCC 12472. Four pure compounds were extracted and identified; of these, methyl gallate (MG) showed the most potent QSI. MG had a minimum inhibitory concentration (MIC) of 512 g/mL against P. aeruginosa strains PAO1, PA14, Pa21, Pa22, Pa23, Pa24, and PAO-JP2. The virulence factors of PAO1, PA14, Pa21, Pa22, Pa23, and Pa24 were significantly inhibited by MG at 1/4 and 1/2 sub-MICs without affecting bacterial viability. Computational insights were performed by docking the MG compound on the LasR receptor, and the QSI behavior of MG was found to be mediated by three hydrogen bonds: Trp60, Arg61, and Thr75. This study indicates the importance of M. indica and MG in the inhibition and modulation of QS and QS-related virulence factors in P. aeruginosa.

Bactericidal effect of Iberin combined with photodynamic antimicrobial chemotherapy against Pseudomonas aeruginosa biofilm cultured on ex vivo wound model

Wounds infected by Pseudomonas aeruginosa (P. aeruginosa) biofilms are characterized by poor healing and by being long lasting. Pyocyanin and pyoverdine are exotoxins that contribute to P. aeruginosa pathogenicity in wound infections and are known as virulence factors. Despite the usefulness of antimicrobial photodynamic therapy (PDT) in the management of wound infections, biofilms are hurdle for microbial photoinactivation. Quorum sensing (QS) is a cell density-dependent chemical signaling system P. aeruginosa uses to regulate biofilm formation and virulence factors production. In the current study, QS attenuation was used in combination with PDT against P. aeruginosa biofilm cultured on skin explant. Iberin is a QS inhibitor that attenuates P. aeruginosa virulence and affects biofilm integrity. The antibiofilm and QS inhibitory activities of iberin in combination with either riboflavin or 5,10,15,20-Tetrakis(1-methyl-4-pyridinio) porphyrin tetra p-toluenesulfonate (TMP) mediated PDT were investigated using viable count method and pyocyanin and pyoverdine assays, respectively.No bactericidal activity was reported when iberin was added to a mature biofilm (24 h) followed by PDT. When added to a growing biofilm at multiple time points (0 h, 24 h and 48 h), iberin inhibited P. aeruginosa biofilm QS signaling system. This inhibitory effect resulted in an observable decrease in the levels of the QS-regulated virulence factors, pyocyanin and pyoverdine, without any effect on the growth of the biofilm cultures. These changes in biofilm virulence were associated with a decrease in biofilm resistance to PDT and caused bactericidal effect upon photosensitizers treatment and irradiation. Iberin-treated-riboflavin-mediated PDT resulted in a significant 1.3 log reduction in biofilm population. Similarly, iberin-treated-TMP-mediated PDT caused a significant 1.8 log reduction in biofilm population. The combination of QS inhibitor with PDT is a promising alternative antimicrobial therapy for the management of biofilms.

Energy exchange in the body of broilers when introducing Quercus cortex extract and chlortetracycline into the diet

Feed antibiotics are widely used in the diet of poultry as growth stimulants, to maintain health and increase productivity. However, their use carries some risks, which leads to a reduction in the use of antibiotics in diets. Therefore, the search for an alternative that can minimize the negative effect of antibacterial substances is a global task. Plants containing phytochemical compounds are of great interest in the search. One of such phytobiotics is oak bark (Quercus cortex), some of its components act as agents of alternative antibacterial strategies (blocking of the Quorum Sensing signaling system (QS)). However, studies on the effects of Quercus cortex are few. It is interesting to study the additional effects of this phytobiotic in combination with other biologically active substances (probiotics, enzymes and antibiotics in small doses). Based on this, the purpose of this work was to evaluate the effect of Quercus cortex extract and Biovit 200 feed antibiotic based on 20% chlortetracycline on energy metabolism in broiler chickens. The study was conducted using generally accepted methods of analyzing metabolic processes in the body of a bird. The calculation of net and exchange energies, energy protein ratio, coefficient of productive use of exchange energy, gross energy was made. The results obtained allow us to conclude that the inclusion of Quercus cortex extract at a dosage of 0,2 ml/kg both independently and in combination with Biovit 200 at a dosage of 0,63 g/kg w.m./ day contributed to a reduction in the amount of energy loss with excrement with an increase in the KPI of OE and the compliance indicator, which shows a more rational use of energy for the process of tissue synthesis in the body of birds of I and III groups.

Design, synthesis, biological evaluation and in silico studies of N-(pyridin-2-yl)-benzamides derivatives as quorum sensing inhibitors

The emergence of bacterial resistance against chemical treatment is a big threat to the efficacy of bacterial infection treatment. One of the major reasons for resistance to antimicrobial agents is growth of microorganisms in biofilm. An alternative treatment by developing novel anti-biofilm agents had led to the concept of quorum sensing (QS) inhibition, which primarily targets QS signaling system by disrupting cell-cell communication. Therefore, this study focuses to develop novel antimicrobial agents which work by QS inhibition and act as anti-biofilm agents against Bacillus Subtilis and Pseudomonas Aeruginosa. In this work, a natural product-like scaffolds from Asinex library were screened and N-pyridin-2-yl-benzamide moiety was chosen to design and synthesize. Synthesized compounds were evaluated for potential anti-biofilm activity for the aforesaid microorganisms and also checked for cell viability assay, where two potent compounds 3a and 3c showed their static biofilm activity to ∼59% and ∼58% at 100 μM, respectively against Bacillus subtilis. These synthesized compounds were investigated for physicochemical parameters and binding mode prediction through molecular modelling tools. The interactions and stability of these compounds showed better affinity towards TasA and LasR proteins from Bacillus subtilis and Pseudomonas aeruginosa, respectively. Furthermore, molecular dynamic simulation for 100 ns was executed in order to appreciate the stability of the protein and ligand complex. The overall results promised that N-pyridin-2-yl-benzamide derivatives can be discovered as a lead in developing potent anti-quorum sensing agents against various bacteria.

Transcriptome analysis revealed the synergism of novel rhodethrin inhibition on biofilm architecture, antibiotic resistance and quorum sensing in Enterococcus faecalis

Enterococcus sp. emerged as an opportunistic nosocomial pathogen with the highest antibiotic resistance and mortality rate. Biofilm is problematic primarily since it is regulated by the global bacterial cell to cell communication mediated by the quorum sensing signaling system. Thus, potential natural antagonists in a novel drug formulation against biofilm-forming Enterococcus faecalis is critical. We used RNA-Seq to evaluate the effects of the novel molecule rhodethrin with chloramphenicol induced on Enterococcus faecalis and DEGs were identified. In transcriptome sequence analysis, a total of 448 with control Vs rhodethrin, 1591 were in control Vs chloramphenicol, 379 genes were DEGs from control Vs synergies, in rhodethrin with chloramphenicol, 379 genes were differentially expressed, whereas 264 genes were significantly downregulated, indicating that 69.69% ofE. faecaliswas altered. The transcriptional sequence data further expression analysis qRT-PCR, and the results shed that the expression profiles of five significant biofilm formation responsible genes such as, Ace, AtpB, lepA, bopD, and typA, 3 genes involved in quorum sensing are sylA, fsrC and camE, and 4 genes involved in resistance were among including liaX, typA, EfrA, and lepA, were significantly suppressed expressions of the biofilm, quorum sensing, and resistance that are supported by transcriptome analysis.

Synthesis, Biological Evaluation and in Silico Study of N-(2- and 3-Pyridinyl)benzamide Derivatives as Quorum Sensing Inhibitors against Pseudomonas aeruginosa.

The effectiveness of treating bacterial infections is seriously threatened by the emergence of bacterial resistance to chemical treatment. Growth of microbes in biofilm is one of the main causes of resistance to antimicrobial drugs. Quorum sensing (QS) inhibition, which targets the QS signalling system by obstructing cell-cell communication, was developed as an alternative treatment by creating innovative anti-biofilm drugs. Therefore, the goal of this study is to develop novel antimicrobial drugs that are effective against Pseudomonas aeruginosa by inhibiting QS and acting as anti-biofilm agents. In this study, N-(2- and 3-pyridinyl)benzamide derivatives were selected to design and syntheses. Antibiofilm activity was revealed by all the synthesized compounds and the biofilm was visibly impaired, and the OD595nm readings of solubilized biofilm cells presented a momentous difference between the treated and untreated biofilms. The best anti-QS zone was observed for compound 5d and found to be 4.96 mm. Through in silico research, the physicochemical characteristics and binding manner of these produced compounds were examined. For the purpose of understanding the stability of the protein and ligand complex, molecular dynamic simulation was also carried out. The overall findings showed that N-(2- and 3-pyridinyl)benzamide derivatives could be the key to creating effective newer anti-quorum sensing drugs that are effective against different bacteria.

Detection of quorum sensing virulence factor genes and its consanguinity to antibiotic sensitivity profile in the clinical isolates of Pseudomonas aeruginosa.

Virulent strains of Pseudomonas aeruginosa exhibit multidrug resistance by intrinsic and extrinsic mechanisms which are regulated by quorum sensing signalling systems. This includes the production of auto-inducers and their transcriptional activators to activate various virulence factors resulting in host infections. The present study is thus aimed to detect the virulence factor production, quorum sensing activity, and susceptibility pattern of P. aeruginosa to antibiotics from clinical specimens. A total of 122 isolates of P. aeruginosa were phenotypically characterized by standard protocols and were categorized into MDR and non-MDR based on the antibiotic susceptibility profiles. Pyocyanin, alkaline protease and elastase production were assessed by qualitative and quantitative methods. Crystal violet assay was carried out for the quantification of biofilms. The genetic determinants of virulence were detected by PCR. Out of the 122 isolates, 80.3% of isolates were MDR and the production of virulence factors was in positive correlation with the presence of genetic determinants and 19.6% were non-MDR, but still showed the production of virulence factors, as confirmed by both phenotypic and genotypic methods. Few carbapenem-resistant strains were detected which did not show the production of virulence factors by both methods. The study concludes, though the strains were non-MDR, they were still capable of producing the virulence factors which may be responsible for the dissemination and chronicity of the infection caused by P. aeruginosa.

Host-Defense-Peptide-Mimicking β-Peptide Polymer Acting as a Dual-Modal Antibacterial Agent by Interfering Quorum Sensing and Killing Individual Bacteria Simultaneously

Host defense peptides (HDPs) are one of the potentially promising agents for infection diseases due to their broad spectrum and low resistance rate, but their clinical applications are limited by proteolytic instability, high-cost, and complicated synthesis process. Here, we report a host-defense-peptide-mimicking β-peptide polymer that resists proteolysis to have enhanced the activity under physiological conditions, excellent antimicrobial efficiency even at high density of bacteria, and low cost for preparation. The β-peptide polymer demonstrated quorum sensing (QS) interference and bactericidal effect against both bacterial communities and individual bacterium to simultaneously block bacterial communication and disrupt bacterial membranes. The hierarchical QS network was suppressed, and main QS signaling systems showed considerably down-regulated gene expression, resulting in excellent biofilm eradication and virulence reduction effects. The dual-modal antibacterial ability possessed excellent therapeutic effects in Pseudomonas aeruginosa pneumonia, which could inhibit biofilm formation and exhibit better antibacterial and anti-inflammatory efficiency than clinically used antibiotics, levofloxacin. Furthermore, the β-peptide polymer also showed excellent therapeutic effect Escherichia coli pyogenic liver abscess. Together, we believed that the β-peptide polymer had a feasible clinical potential to treat bacterial infection diseases.

Novel silver metformin nano-structure to impede virulence of Staphylococcus aureus

Staphylococcus aureus is a prevalent etiological agent of health care associated and community acquired infections. Antibiotic abuse resulted in developing multidrug resistance in S. aureus that complicates treatment of infections. Targeting bacterial virulence using FDA approved medication offers an alternative to the antibiotics with no stress on bacterial viability. Using nanomaterials as anti-virulence agent against S. aureus virulence factors is a valuable approach. This study aims to investigate the impact of metformin (MET), metformin nano (MET-Nano), silver metformin nano structure (Ag-MET-Ns) and silver nanoparticles (AgNPs) on S. aureus virulence and pathogenicity. The in vitro results showed a higher inhibitory activity against S. aureus virulence factors with both MET-Nano and Ag-MET-Ns treatment. However, genotypically, it was found that except for agrA and icaR genes that are upregulated, the tested agents significantly downregulated the expression of crtM, sigB, sarA and fnbA genes, with Ag-MET-Ns being the most efficient one. MET-Nano exhibited the highest protection against S. aureus infection in mice. These data indicate the promising anti-virulence activity of nanoformulations especially Ag-MET-Ns against multidrug resistant S. aureus by inhibiting quorum sensing signaling system.

Amino acid divergence in the ligand-binding pocket of Vibrio LuxR/HapR proteins determines the efficacy of thiophenesulfonamide inhibitors.

The quorum-sensing signaling systems in Vibrio bacteria converge to control levels of the master transcription factors LuxR/HapR, a family of highly conserved proteins that regulate gene expression for bacterial behaviors. A compound library screen identified 2-thiophenesulfonamide compounds that specifically inhibit Vibriocampbellii LuxR but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure-activity relationship effects on Vibrio quorum sensing. The most potent molecule identified, PTSP (3-phenyl-1-(thiophen-2-ylsulfonyl)-1H-pyrazole), inhibits quorum sensing in multiple strains of V.vulnificus, V.parahaemolyticus, and V.campbellii at nanomolar concentrations. However, thiophenesulfonamide inhibition efficacy varies significantly among Vibrio species: PTSP is most inhibitory against V.vulnificus SmcR, but V.cholerae HapR is completely resistant to all thiophenesulfonamides tested. Reverse genetics experiments show that PTSP efficacy is dictated by amino acid sequence in the putative ligand-binding pocket: F75Y and C170F SmcR substitutions are each sufficient to eliminate PTSP inhibition. Further, in silico modeling distinguished the most potent thiophenesulfonamides from less-effective derivatives. Our results revealed the previously unknown differences in LuxR/HapR proteins that control quorum sensing in Vibrio species and underscore the potential for developing thiophenesulfonamides as specific quorum sensing-directed treatments for Vibrio infections.

Design, Synthesis and Biological Evaluation of Novel Anthraniloyl-AMP Mimics as PQS Biosynthesis Inhibitors Against Pseudomonas aeruginosa Resistance.

The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation of PQS biosynthesis. The enzyme anthraniloyl-CoA synthetase (PqsA) catalyzes the first and critical step in the biosynthesis of quinolones; therefore, it is an attractive target for the development of anti-virulence therapeutics against Pseudomonas resistance. Herein, we report the design and synthesis of novel triazole nucleoside-based anthraniloyl- adenosine monophosphate (AMP) mimics. These analogues had a major impact on the morphology of bacterial biofilms and caused significant reduction in bacterial aggregation and population density. However, the compounds showed only limited inhibition of PQS and did not exhibit any effect on pyocyanin production.

Effect of Quorum Sensing Inhibitor Agents against Pseudomonas aeruginosa

The abuse of antibiotics in therapy has lead to the development of resistance in the target organisms. The failure of presented antibiotics to control infections makes it essential to discover option to presently available drugs. Quorum sensing (QS) is a used by many bacteria to regulate gene expression in accordance with population density through the use of signal molecules or autoinducers. The QS is used by Bacteria populations to communicate and coordinate their group interactions, which is applied by pathogens in infection processes. The QS pathways in bacteria are composed of several parts, including bacteria populations, signal molecules, protein activators and target genes. The pathogenicity in numerous bacteria is regulated by QS signaling systems. The QS inhibition system may cause the reduction of virulence and defense against bacterial infections. The QS is the main regulator of virulence and biofilm formation in Pseudomonas aeruginosa and other relevant bacteria. In P. aeruginosa, the expression of many virulence factors appears to be controlled by QS. So, according to the role of this mechanism in the regulation and production of many virulence factors, the function of QS is required for P. aeruginosa to cause disease and infection. In this article, we discussed the QS mechanism in gram-negative and gram-positive bacteria with a closer look at the P. aeruginosa. A variety of plants showed their effects on P. aeruginosa virulence. Extract of various plants control the regulatory QS genes and factors with marginal effects on bacterial growth. The quorum-quenching (QQ) mechanisms are unrelated to static or cidal effects. In fact, anti-QS have already shown promise in the battle against P. aeruginosa infections.