Widespread Existence of Quorum Sensing Inhibitors in Marine Bacteria: Potential Drugs to Combat Pathogens with Novel Strategies

Quorum sensing (QS) is a phenomenon of intercellular communication discovered mainly in bacteria. A QS system consisting of QS signal molecules and regulatory protein components could control physiological behaviors and virulence gene expression of bacterial pathogens. Therefore, QS inhibition could be a novel strategy to combat pathogens and related diseases. QS inhibitors (QSIs), mainly categorized into small chemical molecules and quorum quenching enzymes, could be extracted from diverse sources in marine environment and terrestrial environment. With the focus on the exploitation of marine resources in recent years, more and more QSIs from the marine environment have been investigated. In this article, we present a comprehensive review of QSIs from marine bacteria. Firstly, screening work of marine bacteria with potential QSIs was concluded and these marine bacteria were classified. Afterwards, two categories of marine bacteria-derived QSIs were summarized from the aspects of sources, structures, QS inhibition mechanisms, environmental tolerance, effects/applications, etc. Next, structural modification of natural small molecule QSIs for future drug development was discussed. Finally, potential applications of QSIs from marine bacteria in human healthcare, aquaculture, crop cultivation, etc. were elucidated, indicating promising and extensive application perspectives of QS disruption as a novel antimicrobial strategy.

Download Full-text

Advancing the Quorum in Pseudomonas aeruginosa: MvaT and the Regulation of N-Acylhomoserine Lactone Production and Virulence Gene Expression

Journal of Bacteriology ◽

10.1128/jb.184.10.2576-2586.2002 ◽

2002 ◽

Vol 184 (10) ◽

pp. 2576-2586 ◽

Cited By ~ 182

Author(s):

Stephen P. Diggle ◽

Klaus Winzer ◽

Andrée Lazdunski ◽

Paul Williams ◽

Miguel Cámara

Keyword(s):

Gene Expression ◽

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Growth Phase ◽

Virulence Gene ◽

Homoserine Lactone ◽

Logarithmic Phase ◽

Signal Molecules ◽

Virulence Gene Expression ◽

Acylhomoserine Lactone

ABSTRACT Pseudomonas aeruginosa regulates the production of many exoproteins and secondary metabolites via a hierarchical quorum-sensing cascade through LasR and RhlR and their cognate signal molecules N-(3-oxododecanoyl)-l-homoserine lactone (3O-C12-HSL) and N-(butanoyl)-l-homoserine lactone (C4-HSL). In this study, we found that transcription of the quorum sensing-regulated genes lecA (coding for PA-IL lectin), lasB (coding for elastase), and rpoS appeared to be growth phase dependent and their expression could not be advanced to the logarithmic phase in cells growing in batch culture by the addition of exogenous C4-HSL and 3O-C12-HSL. To identify novel regulators responsible for this growth phase dependency, a P. aeruginosa lecA::lux reporter strain was subjected to random transposon mutagenesis. A number of mutants affected in lecA expression were found that exhibited altered production of multiple quorum sensing-dependent phenotypes. While some mutations were mapped to new loci such as clpA and mvaT and a putative efflux system, a number of mutations were also mapped to known regulators such as lasR, rhlR, and rpoS. MvaT was identified as a novel global regulator of virulence gene expression, as a mutation in mvaT resulted in enhanced lecA expression and pyocyanin production. This mutant also showed altered swarming ability and production of the LasB and LasA proteases, 3O-C12-HSL, and C4-HSL. Furthermore, addition of exogenous 3O-C12-HSL and C4-HSL to the mvaT mutant significantly advanced lecA expression, suggesting that MvaT is involved in the growth phase-dependent regulation of the lecA gene.

Download Full-text

Crystal Structure of the Vibrio cholerae Quorum-Sensing Regulatory Protein HapR

Journal of Bacteriology ◽

10.1128/jb.01807-06 ◽

2007 ◽

Vol 189 (15) ◽

pp. 5683-5691 ◽

Cited By ~ 44

Author(s):

Rukman S. De Silva ◽

Gabriela Kovacikova ◽

Wei Lin ◽

Ronald K. Taylor ◽

Karen Skorupski ◽

...

Keyword(s):

Gene Expression ◽

Crystal Structure ◽

Dna Binding ◽

Quorum Sensing ◽

Vibrio Cholerae ◽

Biofilm Formation ◽

Regulatory Protein ◽

Virulence Gene ◽

Binding Motif ◽

Virulence Gene Expression

ABSTRACT Quorum sensing in Vibrio cholerae involves signaling between two-component sensor protein kinases and the response regulator LuxO to control the expression of the master regulator HapR. HapR, in turn, plays a central role in regulating a number of important processes, such as virulence gene expression and biofilm formation. We have determined the crystal structure of HapR to 2.2-Å resolution. Its structure reveals a dimeric, two-domain molecule with an all-helical structure that is strongly conserved with members of the TetR family of transcriptional regulators. The N-terminal DNA-binding domain contains a helix-turn-helix DNA-binding motif and alteration of certain residues in this domain completely abolishes the ability of HapR to bind to DNA, alleviating repression of both virulence gene expression and biofilm formation. The C-terminal dimerization domain contains a unique solvent accessible tunnel connected to an amphipathic cavity, which by analogy with other TetR regulators, may serve as a binding pocket for an as-yet-unidentified ligand.

Download Full-text

Quorum sensing in bacterial virulence

Microbiology ◽

10.1099/mic.0.038794-0 ◽

2010 ◽

Vol 156 (8) ◽

pp. 2271-2282 ◽

Cited By ~ 321

Author(s):

L. Caetano M. Antunes ◽

Rosana B. R. Ferreira ◽

Michelle M. C. Buckner ◽

B. Brett Finlay

Keyword(s):

Gene Expression ◽

Quorum Sensing ◽

Target Genes ◽

Critical Concentration ◽

Virulence Gene ◽

Bacterial Virulence ◽

Signal Molecules ◽

Control Of Gene Expression ◽

Virulence Gene Expression

Bacteria communicate through the production of diffusible signal molecules termed autoinducers. The molecules are produced at basal levels and accumulate during growth. Once a critical concentration has been reached, autoinducers can activate or repress a number of target genes. Because the control of gene expression by autoinducers is cell-density-dependent, this phenomenon has been called quorum sensing. Quorum sensing controls virulence gene expression in numerous micro-organisms. In some cases, this phenomenon has proven relevant for bacterial virulence in vivo. In this article, we provide a few examples to illustrate how quorum sensing can act to control bacterial virulence in a multitude of ways. Several classes of autoinducers have been described to date and we present examples of how each of the major types of autoinducer can be involved in bacterial virulence. As quorum sensing controls virulence, it has been considered an attractive target for the development of new therapeutic strategies. We discuss some of the new strategies to combat bacterial virulence based on the inhibition of bacterial quorum sensing systems.

Download Full-text

Photo sensing and quorum sensing are integrated to control bacterial group behaviors

10.1101/747618 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sampriti Mukherjee ◽

Matthew Jemielita ◽

Vasiliki Stergioula ◽

Mikhail Tikhonov ◽

Bonnie L. Bassler

Keyword(s):

Quorum Sensing ◽

Biofilm Formation ◽

Response Regulator ◽

Sensory Information ◽

Virulence Gene ◽

Component System ◽

Virulence Gene Expression ◽

Bacterial Phyla ◽

Expression Of Genes ◽

Genes Encoding

ABSTRACTPseudomonas aeruginosa transitions between the free-swimming state and the sessile biofilm mode during its pathogenic lifestyle. We show that quorum sensing represses P. aeruginosa biofilm formation and virulence by activating expression of genes encoding the KinB-AlgB two-component system. Phospho-AlgB represses biofilm and virulence genes, while KinB dephosphorylates, and thereby, inactivates AlgB. We discover that the photoreceptor BphP is the kinase that, in response to light, phosphorylates and activates AlgB. Indeed, exposing P. aeruginosa to light represses biofilm formation and virulence gene expression. To our knowledge, P. aeruginosa was not previously known to detect light. The KinB-AlgB-BphP module is present in all Pseudomonads, and we demonstrate that AlgB is the cognate response regulator for BphP in diverse bacterial phyla. We propose that KinB-AlgB-BphP constitutes a “three-component” system and AlgB is the node at which varied sensory information is integrated. This study sets the stage for light-mediated control of P. aeruginosa infectivity.

Download Full-text

Interference with Pseudomonas aeruginosa Quorum Sensing and Virulence by the Mycobacterial Pseudomonas Quinolone Signal Dioxygenase AqdC in Combination with the N-Acylhomoserine Lactone Lactonase QsdA

Infection and Immunity ◽

10.1128/iai.00278-19 ◽

2019 ◽

Vol 87 (10) ◽

Cited By ~ 4

Author(s):

Franziska S. Birmes ◽

Ruth Säring ◽

Miriam C. Hauke ◽

Niklas H. Ritzmann ◽

Steffen L. Drees ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Virulence Factors ◽

Rhodococcus Erythropolis ◽

Quorum Quenching ◽

Signal Molecules ◽

Content Type ◽

Acylhomoserine Lactone ◽

Regulatory Effects ◽

Epithelial Lung Cells

ABSTRACT The nosocomial pathogen Pseudomonas aeruginosa regulates its virulence via a complex quorum sensing network, which, besides N-acylhomoserine lactones, includes the alkylquinolone signal molecules 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal [PQS]) and 2-heptyl-4(1H)-quinolone (HHQ). Mycobacteroides abscessus subsp. abscessus, an emerging pathogen, is capable of degrading the PQS and also HHQ. Here, we show that although M. abscessus subsp. abscessus reduced PQS levels in coculture with P. aeruginosa PAO1, this did not suffice for quenching the production of the virulence factors pyocyanin, pyoverdine, and rhamnolipids. However, the levels of these virulence factors were reduced in cocultures of P. aeruginosa PAO1 with recombinant M. abscessus subsp. massiliense overexpressing the PQS dioxygenase gene aqdC of M. abscessus subsp. abscessus, corroborating the potential of AqdC as a quorum quenching enzyme. When added extracellularly to P. aeruginosa cultures, AqdC quenched alkylquinolone and pyocyanin production but induced an increase in elastase levels. When supplementing P. aeruginosa cultures with QsdA, an enzyme from Rhodococcus erythropolis which inactivates N-acylhomoserine lactone signals, rhamnolipid and elastase levels were quenched, but HHQ and pyocyanin synthesis was promoted. Thus, single quorum quenching enzymes, targeting individual circuits within a complex quorum sensing network, may also elicit undesirable regulatory effects. Supernatants of P. aeruginosa cultures grown in the presence of AqdC, QsdA, or both enzymes were less cytotoxic to human epithelial lung cells than supernatants of untreated cultures. Furthermore, the combination of both aqdC and qsdA in P. aeruginosa resulted in a decline of Caenorhabditis elegans mortality under P. aeruginosa exposure.

Download Full-text

Integration of Cyclic di-GMP and Quorum Sensing in the Control ofvpsTandaphAin Vibrio cholerae

Journal of Bacteriology ◽

10.1128/jb.05167-11 ◽

2011 ◽

Vol 193 (22) ◽

pp. 6331-6341 ◽

Cited By ~ 103

Author(s):

Disha Srivastava ◽

Rebecca C. Harris ◽

Christopher M. Waters

Keyword(s):

Quorum Sensing ◽

Binding Site ◽

Vibrio Cholerae ◽

Biofilm Formation ◽

Virulence Gene ◽

Transcriptional Activator ◽

Transcriptional Regulators ◽

Content Type ◽

Virulence Gene Expression ◽

Signaling Systems

Vibrio choleraetransitions between aquatic environmental reservoirs and infection in the gastrointestinal tracts of human hosts. The second-messenger molecule cyclic di-GMP (c-di-GMP) and quorum sensing (QS) are important signaling systems that enableV. choleraeto alternate between these distinct environments by controlling biofilm formation and virulence factor expression. Here we identify a conserved regulatory mechanism inV. choleraethat integrates c-di-GMP and QS to control the expression of two transcriptional regulators:aphA, an activator of virulence gene expression and an important regulator of the quorum-sensing pathway, andvpsT, a transcriptional activator that induces biofilm formation. Surprisingly,aphAexpression was induced by c-di-GMP. Activation of bothaphAandvpsTby c-di-GMP requires the transcriptional activator VpsR, which binds to c-di-GMP. The VpsR binding site at each of these promoters overlaps with the binding site of HapR, the master QS regulator at high cell densities. Our results suggest thatV. choleraecombines information conveyed by QS and c-di-GMP to appropriately respond and adapt to divergent environments by modulating the expression of key transcriptional regulators.

Download Full-text

Novel Reporter for Identification of Interference with Acyl Homoserine Lactone and Autoinducer-2 Quorum Sensing

Applied and Environmental Microbiology ◽

10.1128/aem.03290-14 ◽

2014 ◽

Vol 81 (4) ◽

pp. 1477-1489 ◽

Cited By ~ 28

Author(s):

Nancy Weiland-Bräuer ◽

Nicole Pinnow ◽

Ruth A. Schmitz

Keyword(s):

Quorum Sensing ◽

Vibrio Fischeri ◽

Quorum Quenching ◽

Homoserine Lactone ◽

Signal Molecules ◽

Lethal Gene ◽

Reporter Strain ◽

Content Type ◽

E Coli ◽

Autoinducer 2

ABSTRACTTwo reporter strains were established to identify novel biomolecules interfering with bacterial communication (quorum sensing [QS]). The basic design of theseEscherichia coli-based systems comprises a gene encoding a lethal protein fused to promoters induced in the presence of QS signal molecules. Consequently, theseE. colistrains are unable to grow in the presence of the respective QS signal molecules unless a nontoxic QS-interfering compound is present. The first reporter strain designed to detect autoinducer-2 (AI-2)-interfering activities (AI2-QQ.1) contained theE. coliccdBlethal gene under the control of theE. colilsrApromoter. The second reporter strain (AI1-QQ.1) contained theVibrio fischeriluxIpromoter fused to theccdBgene to detect interference with acyl-homoserine lactones. Bacteria isolated from the surfaces of several marine eukarya were screened for quorum-quenching (QQ) activities using the established reporter systems AI1-QQ.1 and AI2-QQ.1. Out of 34 isolates, two interfered with acylated homoserine lactone (AHL) signaling, five interfered with AI-2 QS signaling, and 10 were demonstrated to interfere with both signal molecules. Open reading frames (ORFs) conferring QQ activity were identified for three selected isolates (Photobacteriumsp.,Pseudoalteromonassp., andVibrio parahaemolyticus). Evaluation of the respective heterologously expressed and purified QQ proteins confirmed their ability to interfere with the AHL and AI-2 signaling processes.

Download Full-text

Staphylococcus aureus CodY Negatively Regulates Virulence Gene Expression

Journal of Bacteriology ◽

10.1128/jb.01545-07 ◽

2007 ◽

Vol 190 (7) ◽

pp. 2257-2265 ◽

Cited By ~ 120

Author(s):

Charlotte D. Majerczyk ◽

Marat R. Sadykov ◽

Thanh T. Luong ◽

Chia Lee ◽

Greg A. Somerville ◽

...

Keyword(s):

Gene Expression ◽

Staphylococcus Aureus ◽

Regulatory Protein ◽

Virulence Gene ◽

Culture Fluid ◽

Accessory Gene ◽

Virulence Gene Expression ◽

Gram Positive Bacteria ◽

Accessory Gene Regulator ◽

Branched Chain

ABSTRACT CodY is a global regulatory protein that was first discovered in Bacillus subtilis, where it couples gene expression to changes in the pools of critical metabolites through its activation by GTP and branched-chain amino acids. Homologs of CodY can be found encoded in the genomes of nearly all low-G+C gram-positive bacteria, including Staphylococcus aureus. The introduction of a codY-null mutation into two S. aureus clinical isolates, SA564 and UAMS-1, through allelic replacement, resulted in the overexpression of several virulence genes. The mutant strains had higher levels of hemolytic activity toward rabbit erythrocytes in their culture fluid, produced more polysaccharide intercellular adhesin (PIA), and formed more robust biofilms than did their isogenic parent strains. These phenotypes were associated with derepressed levels of RNA for the hemolytic alpha-toxin (hla), the accessory gene regulator (agr) (RNAII and RNAIII/hld), and the operon responsible for the production of PIA (icaADBC). These data suggest that CodY represses, either directly or indirectly, the synthesis of a number of virulence factors of S. aureus.

Download Full-text

The in Vitro Antibiofilm Activity of Waterfall and Marine Bacteria Against Human Bacterial Pathogens

AL-Kauniyah Jurnal Biologi ◽

10.15408/kauniyah.v13i2.14926 ◽

2020 ◽

Vol 13 (2) ◽

pp. 250-262

Author(s):

Stella Magdalena ◽

Natassa Rustandi ◽

Yogiara Yogiara

Keyword(s):

Quorum Sensing ◽

16S Rrna ◽

Bioactive Compounds ◽

Marine Bacteria ◽

Bacterial Pathogens ◽

Quorum Quenching ◽

Health Concern ◽

Effective Control ◽

Antibiofilm Activity ◽

Antibiofilm Agents

AbstrakKeterlibatan biofilm pada infeksi kronis dan pada permukaan peralatan medis selalu menjadi wacana penting bagi kesehatan umum di dunia. Biofilm bakteri berkaitan dengan tingkat resistensi terhadap antibiotik yang menjadikan infeksi sulit untuk diobati. Untuk mengatasi masalah ini, pengendalian yang efektif perlu diimplementasikan, seperti penerapan senyawa antibiofilm. Beberapa tahun terakhir, lingkungan akuatik menjadi salah satu sumber potensi penghasil senyawa bioaktif, termasuk senyawa antibiofilm. Tujuan dari penelitian ini yaitu menapis dan mengkarakterisasi bakteri asal air terjun dan laut yang diperoleh dari beberapa lokasi di Indonesia, sebagai penghasil aktivitas antibiofilm. Isolat dievaluasi berdasarkan kemampuan aktivitas antimikroba terhadap enam bakteri patogen dan diikuti dengan penapisan senyawa antibiofilm. Sebanyak 11 dari 65 isolat menunjukkan aktivitas quorum sensing atau quorum quenching, dan hanya terdapat satu isolat yang memiliki aktivitas keduanya. Supernatan kesebelas isolat menunjukkan penghambatan pembentukan biofilm setidaknya terhadap satu patogen dengan metode uji biofilm statis. Karakterisasi senyawa bioaktif dari lima isolat yang terpilih menunjukkan aktivitas senyawa yang berbeda, seperti karbohidrat, protein, dan asam nukleat. Sekuensing gen penyandi 16S rRNA menetapkan kelima isolat tersebut berada dalam dua genus yang berbeda, Vibrio (WK2.4, WK2.6, and WK2.3) dan Pseudomonas (S1.2 dan S1.3). Penelitian ini memberikan wawasan baru terhadap pencarian kandidat bakteri akuatik sebagai agen antibiofilm yang potensial. Abstract Biofilm involvement in chronic infections and on the surface of medical equipments have been considered as public health concern worldwide. Bacterial biofilm is related to antibiotic resistance that made the diseases difficult to treat. An effective control strategy should be implemented, for example, by applying antibiofilm agents. Recently, concerns has been given to aquatic environment as potential sources of bioactive compounds, including the antibiofilm compounds. This study aimed to screen and characterize waterfall and marine bacteria obtained from several locations in Indonesia which have antibiofilm activity. The isolates were first evaluated for their antimicrobial activity against six bacterial pathogens and followed by antibiofilm screening. Eleven out of 65 isolates showed quorum sensing or quorum quenching activity, and one of them showed both activities. Supernatants of 11 isolates inhibited biofilm formation of at least one pathogen by using static biofilm assay. Bioactive compounds characterization of the selected five isolates revealed the presence of different compounds, such as carbohydrates, proteins, and nucleic acids. The 16S rRNA gene sequencing analysis classified five isolates into two different genera, Vibrio (WK2.4, WK2.6, and WK2.3) and Pseudomonas (S1.2 and S1.3). The present study provides insights into the discovery of aquatic bacteria candidates as antibiofilm agents.

Download Full-text