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Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics

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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 48526

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Prof. Dr. Valeria Costantino

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Department of Pharmacy, University of Naples Federico II, Via Montesano 149, 80131 Naples, Italy
Interests: isolation and stereostructural elucidation of new leads compounds in anti-inflammatory and anti-cancer drug discovery; exploration of the QQ and the QS system in bacteria symbiotic with sponges with the goal to create novel leads in antibacterial drug discovery; cyanobacteria as source of novel lead compounds and toxins
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Dear Colleagues,

It is well recognized that bacteria are able to communicate with each other using a cell-signaling system, known as “quorum sensing” (QS). The “language” that bacteria use to communicate is the use of small signaling molecules, enabling them to activate a variety of processes, including the biosynthesis of virulence factors, and biofilm formation in a synchronized, population-density-dependent manner. The discovery that QS controls the production of virulence factors and biofilm formation in many common nosocomial pathogens has opened the way for research looking at novel agents able to interfere with the QS mechanism, with the idea of developing novel ways to fight and/or control bacterial infections, other than by using antibiotics.

In recent years, the need to find alternatives to antibiotics has raised the level of emergency, due to the increasing occurrence of resistant strains that have enormous consequences for human lives and economic impact. The marine world represents an excellent source to isolate bioactive compounds that are able to interfere with the QS system, i.e. quorum quenching (QQ) agents, and, at the same time, to identify novel chemical tools to develop studies on QS mechanisms and their regulation.

This Special Issue of Marine Drugs will cover the entire field of marine QS and QQ agents. In particular, studies on the molecular mechanisms of these compounds are especially encouraged.

Prof. Valeria Costantino
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Quorum sensing
Quorum quenching agents
Autoinducers
N-acyl homoserine lactones
Marine bacteria
Antivirulance lead compounds
LuxR homologues
LuxI homologues
Diketopiperazines
Peptide signalling molecules

Related Special Issue

Quorum Sensing Bacterial Communication Systems and Interference Strategies in Marine Environments in Marine Drugs (5 articles)

Published Papers (10 papers)

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Research

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14 pages, 1008 KiB

Open AccessArticle

Identification of Quorum Sensing Activators and Inhibitors in The Marine Sponge Sarcotragus spinosulus

by Kumar Saurav, Nicola Borbone, Ilia Burgsdorf, Roberta Teta, Alessia Caso, Rinat Bar-Shalom, Germana Esposito, Maya Britstein, Laura Steindler and Valeria Costantino

Mar. Drugs 2020, 18(2), 127; https://doi.org/10.3390/md18020127 - 20 Feb 2020

Cited by 17 | Viewed by 4097

Abstract

Marine sponges, a well-documented prolific source of natural products, harbor highly diverse microbial communities. Their extracts were previously shown to contain quorum sensing (QS) signal molecules of the N-acyl homoserine lactone (AHL) type, known to orchestrate bacterial gene regulation. Some bacteria and eukaryotic organisms are known to produce molecules that can interfere with QS signaling, thus affecting microbial genetic regulation and function. In the present study, we established the production of both QS signal molecules as well as QS inhibitory (QSI) molecules in the sponge species Sarcotragus spinosulus. A total of eighteen saturated acyl chain AHLs were identified along with six unsaturated acyl chain AHLs. Bioassay-guided purification led to the isolation of two brominated metabolites with QSI activity. The structures of these compounds were elucidated by comparative spectral analysis of ¹HNMR and HR-MS data and were identified as 3-bromo-4-methoxyphenethylamine (1) and 5,6-dibromo-N,N-dimethyltryptamine (2). The QSI activity of compounds 1 and 2 was evaluated using reporter gene assays for long- and short-chain AHL signals (Escherichia coli pSB1075 and E. coli pSB401, respectively). QSI activity was further confirmed by measuring dose-dependent inhibition of proteolytic activity and pyocyanin production in Pseudomonas aeruginosa PAO1. The obtained results show the coexistence of QS and QSI in S. spinosulus, a complex signal network that may mediate the orchestrated function of the microbiome within the sponge holobiont. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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7 pages, 858 KiB

Open AccessArticle

Altertoxins with Quorum Sensing Inhibitory Activities from The Marine-Derived Fungus Cladosporium sp. KFD33

by Fei Zhang, Liman Zhou, Fandong Kong, Qingyun Ma, Qingyi Xie, Jiuhui Li, Haofu Dai, Lei Guo and Youxing Zhao

Mar. Drugs 2020, 18(1), 67; https://doi.org/10.3390/md18010067 - 19 Jan 2020

Cited by 23 | Viewed by 3028

Abstract

Five new perylenequinone derivatives, altertoxins VIII–XII (1–5), as well as one known compound cladosporol I (6), were isolated from the fermentation broth of the marine-derived fungus Cladosporium sp. KFD33 from a blood cockle from Haikou Bay, China. Their structures were determined based on spectroscopic methods and ECD spectra analysis along with quantum ECD calculations. Compounds 1–6 exhibited quorum sensing inhibitory activities against Chromobacterium violaceum CV026 with MIC values of 30, 30, 20, 30, 20 and 30 μg/well, respectively. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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18 pages, 8707 KiB

Open AccessArticle

A Quorum-Sensing Inhibitor Strain of Vibrio alginolyticus Blocks Qs-Controlled Phenotypes in Chromobacterium violaceum and Pseudomonas aeruginosa

by José Carlos Reina, Ignacio Pérez-Victoria, Jesús Martín and Inmaculada Llamas

Mar. Drugs 2019, 17(9), 494; https://doi.org/10.3390/md17090494 - 24 Aug 2019

Cited by 23 | Viewed by 4368

Abstract

The cell density-dependent mechanism, quorum sensing (QS), regulates the expression of virulence factors. Its inhibition has been proposed as a promising new strategy to prevent bacterial pathogenicity. In this study, 827 strains from the microbiota of sea anemones and holothurians were screened for their ability to produce quorum-sensing inhibitor (QSI) compounds. The strain M3-10, identified as Vibrio alginolyticus by 16S rRNA gene sequencing, as well as ANIb and dDDH analyses, was selected for its high QSI activity. Bioassay-guided fractionation of the cell pellet extract from a fermentation broth of strain M3-10, followed by LC–MS and NMR analyses, revealed tyramine and N-acetyltyramine as the active compounds. The QS inhibitory activity of these molecules, which was confirmed using pure commercially available standards, was found to significantly inhibit Chromobacterium violaceum ATCC 12472 violacein production and virulence factors, such as pyoverdine production, as well as swarming and twitching motilities, produced by Pseudomonas aeruginosa PAO1. This constitutes the first study to screen QSI-producing strains in the microbiota of anemones and holothurians and provides an insight into the use of naturally produced QSI as a possible strategy to combat bacterial infections. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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13 pages, 974 KiB

Open AccessCommunication

Antagonism of Quorum Sensing Phenotypes by Analogs of the Marine Bacterial Secondary Metabolite 3-Methyl-N-(2′-Phenylethyl)-Butyramide

by Susan M. Meschwitz, Margaret E. Teasdale, Ann Mozzer, Nicole Martin, Jiayuan Liu, Stephanie Forschner-Dancause and David C. Rowley

Mar. Drugs 2019, 17(7), 389; https://doi.org/10.3390/md17070389 - 01 Jul 2019

Cited by 8 | Viewed by 3360

Abstract

Quorum sensing (QS) antagonists have been proposed as novel therapeutic agents to combat bacterial infections. We previously reported that the secondary metabolite 3-methyl-N-(2′-phenylethyl)-butyramide, produced by a marine bacterium identified as Halobacillus salinus, inhibits QS controlled phenotypes in multiple Gram-negative reporter strains. Here we report that N-phenethyl hexanamide, a structurally-related compound produced by the marine bacterium Vibrio neptunius, similarly demonstrates QS inhibitory properties. To more fully explore structure–activity relationships within this new class of QS inhibitors, a panel of twenty analogs was synthesized and biologically evaluated. Several compounds were identified with increased attenuation of QS-regulated phenotypes, most notably N-(4-fluorophenyl)-3-phenylpropanamide against the marine pathogen Vibrio harveyi (IC₅₀ = 1.1 µM). These findings support the opportunity to further develop substituted phenethylamides as QS inhibitors. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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18 pages, 4004 KiB

Open AccessArticle

Heterologous Expression of the Marine-Derived Quorum Quenching Enzyme MomL Can Expand the Antibacterial Spectrum of Bacillus brevis

by Jingjing Zhang, Jiayi Wang, Tao Feng, Rui Du, Xiaorong Tian, Yan Wang and Xiao-Hua Zhang

Mar. Drugs 2019, 17(2), 128; https://doi.org/10.3390/md17020128 - 21 Feb 2019

Cited by 12 | Viewed by 4096

Abstract

Quorum sensing (QS) is closely associated with the production of multiple virulence factors in bacterial pathogens. N-acyl homoserine lactones (AHLs) are important QS signal molecules that modulate the virulence of gram-negative pathogenic bacteria. Enzymatic degradation of AHLs to interrupt QS, termed quorum quenching (QQ), has been considered a novel strategy for reduction of pathogenicity and prevention of bacterial disease. However, the low expression levels of QQ proteins in the original host bacteria has affected the applications of these proteins. Previously, we identified a novel marine QQ enzyme, named MomL, with high activity and promising biocontrol function. In this study, we linked the target fragment momL to pNCMO2, which provided a basis for the first heterologous expression of MomL in the antifungal and anti-gram-positive-bacteria biocontrol strain Bacillus brevis, and obtaining the recombinant strain named BbMomL. The QQ activity of BbMomL was confirmed using a series of bioassays. BbMomL could not only degrade the exogenous signal molecule C6-HSL, but also the AHL signal molecules produced by the gram-negative pathogens Pectobacterium carotovorum subsp. carotovorum (Pcc) and Pseudomonas aeruginosa PAO1. In addition, BbMomL significantly reduced the secretion of pathogenic factors and the pathogenicity of Pcc and P. aeruginosa PAO1. We tested the biocontrol function of BbMomL for prevention of plant diseases in vitro. The result indicates that BbMomL has a broad antibacterial spectrum. Compared with wild-type B. brevis, BbMomL not only inhibited fungi and gram-positive bacterial pathogens but also considerably inhibited gram-negative bacterial pathogens. Moreover, the Bacillus brevis expression system has good application prospects and is an ideal host for expression and secretion of foreign proteins. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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11 pages, 7049 KiB

Open AccessArticle

Characterization of a Novel N-Acylhomoserine Lactonase RmmL from Ruegeria mobilis YJ3

by Xiulei Cai, Min Yu, Hu Shan, Xiaorong Tian, Yanfen Zheng, Chunxu Xue and Xiao-Hua Zhang

Mar. Drugs 2018, 16(10), 370; https://doi.org/10.3390/md16100370 - 08 Oct 2018

Cited by 15 | Viewed by 4252

Abstract

Gram-negative bacteria utilize N-acylhomoserine lactones (AHLs) as quorum sensing (QS) signaling molecules for intercellular communication. Cell-to-cell communication depends on cell population density, and AHL-dependent QS is related to the production of multiple genes including virulence factors. Quorum quenching (QQ), signal inactivation by enzymatic degradation, is a potential strategy for attenuating QS regulated bacterial infections. Both Gram-positive and -negative bacteria have QQ enzymes that can degrade AHLs. In our previous study, strain Ruegeria mobilis YJ3, isolated from healthy shrimp, showed strong AHLs degradative activity. In the current study, an AHL lactonase (designated RmmL) was cloned and characterized from Ruegeria mobilis YJ3. Amino acid sequence analysis showed that RmmL has a conserved “HXHXDH” motif and clusters together with lactonase AidC that belongs to the metallo-β-lactamase superfamily. Recombinant RmmL could degrade either short- or long-chain AHLs in vitro. High-performance liquid chromatography analysis indicated that RmmL works as an AHL lactonase catalyzing AHL ring-opening by hydrolyzing lactones. Furthermore, RmmL can reduce the production of pyocyanin by Pseudomonas aeruginosa PAO1, while for the violacein and the extracellular protease activities by Chromobacterium violaceum CV026 and Vibrio anguillarum VIB72, no significant reduction was observed. This study suggests that RmmL might be used as a therapeutic agent in aquaculture. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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9 pages, 1237 KiB

Open AccessCommunication

Isolation of Smenopyrone, a Bis-γ-Pyrone Polypropionate from the Caribbean Sponge Smenospongia aurea

by Germana Esposito, Roberta Teta, Gerardo Della Sala, Joseph R. Pawlik, Alfonso Mangoni and Valeria Costantino

Mar. Drugs 2018, 16(8), 285; https://doi.org/10.3390/md16080285 - 17 Aug 2018

Cited by 10 | Viewed by 4084

Abstract

The organic extract of the Caribbean sponge Smenospongia aurea has been shown to contain an array of novel chlorinated secondary metabolites derived from a mixed PKS-NRPS biogenetic route such as the smenamides. In this paper, we report the presence of a biogenetically different compound known as smenopyrone, which is a polypropionate containing two γ-pyrone rings. The structure of smenopyrone including its relative and absolute stereochemistry was determined by spectroscopic analysis (NMR, MS, ECD) and supported by a comparison with model compounds from research studies. Pyrone polypropionates are unprecedented in marine sponges but are commonly found in marine mollusks where their biosynthesis by symbiotic bacteria has been hypothesized and at least in one case demonstrated. Since pyrones have recently been recognized as bacterial signaling molecules, we speculate that smenopyrone could mediate inter-kingdom chemical communication between S. aurea and its symbiotic bacteria. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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Review

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25 pages, 2448 KiB

Open AccessReview

Quorum Sensing Inhibition by Marine Bacteria

by Anabela Borges and Manuel Simões

Mar. Drugs 2019, 17(7), 427; https://doi.org/10.3390/md17070427 - 23 Jul 2019

Cited by 53 | Viewed by 8815

Abstract

Antibiotic resistance has been increasingly reported for a wide variety of bacteria of clinical significance. This widespread problem constitutes one of the greatest challenges of the twenty-first century. Faced with this issue, clinicians and researchers have been persuaded to design novel strategies in order to try to control pathogenic bacteria. Therefore, the discovery and elucidation of the mechanisms underlying bacterial pathogenesis and intercellular communication have opened new perspectives for the development of alternative approaches. Antipathogenic and/or antivirulence therapies based on the interruption of quorum sensing pathways are one of several such promising strategies aimed at disarming rather than at eradicating bacterial pathogens during the course of colonization and infection. This review describes mechanisms of bacterial communication involved in biofilm formation. An overview of the potential of marine bacteria and their bioactive components as QS inhibitors is further provided. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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21 pages, 5773 KiB

Open AccessReview

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

by Jing Zhao, Xinyun Li, Xiyan Hou, Chunshan Quan and Ming Chen

Mar. Drugs 2019, 17(5), 275; https://doi.org/10.3390/md17050275 - 08 May 2019

Cited by 31 | Viewed by 5101

Abstract

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. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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28 pages, 1725 KiB

Open AccessReview

Saline Environments as a Source of Potential Quorum Sensing Disruptors to Control Bacterial Infections: A Review

by Marta Torres, Yves Dessaux and Inmaculada Llamas

Mar. Drugs 2019, 17(3), 191; https://doi.org/10.3390/md17030191 - 25 Mar 2019

Cited by 30 | Viewed by 6334

Abstract

Saline environments, such as marine and hypersaline habitats, are widely distributed around the world. They include sea waters, saline lakes, solar salterns, or hypersaline soils. The bacteria that live in these habitats produce and develop unique bioactive molecules and physiological pathways to cope with the stress conditions generated by these environments. They have been described to produce compounds with properties that differ from those found in non-saline habitats. In the last decades, the ability to disrupt quorum-sensing (QS) intercellular communication systems has been identified in many marine organisms, including bacteria. The two main mechanisms of QS interference, i.e., quorum sensing inhibition (QSI) and quorum quenching (QQ), appear to be a more frequent phenomenon in marine aquatic environments than in soils. However, data concerning bacteria from hypersaline habitats is scarce. Salt-tolerant QSI compounds and QQ enzymes may be of interest to interfere with QS-regulated bacterial functions, including virulence, in sectors such as aquaculture or agriculture where salinity is a serious environmental issue. This review provides a global overview of the main works related to QS interruption in saline environments as well as the derived biotechnological applications. Full article

(This article belongs to the Special Issue Quorum Quenching Agents: Exploring Quorum Sensing Interfering Strategies in Marine Bacteria for the Development of Novel Therapeutics)

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