A REVIEW ON QUORUM SENSING INHIBITORS

A REVIEW ON QUORUM SENSING INHIBITORS

Kaushik Sarkar and Rajesh Kumar Das ^*

Department of Chemistry, University of North Bengal, Raja Rammohunpur, Darjeeling - 734013, West Bengal, India.

ABSTRACT: Antibiotic is the powerful invention of science to damage bacterial infections. But nowadays, the use of careless increasing doses of this antibiotic has led to increasing the resistant power of enemy bacteria. Bacteria are caused by many infectious diseases by proliferation within quorum sensing (QS) mediated biofilms. Quorum sensing can develop microbial pathogenic traits, including biofilm formation. Try to smash biofilms have led the identification of bioactive molecules evolved by prokaryotes and eukaryotes. The activity of these bioactive molecules is done by quenching the QS systems. For this reason, we need to inhibit quorum sensing, which may be done by various types of inhibitors called quorum sensing inhibitors (QSI). Synthetic and natural QSIs plays a vital role to inhibit QS. In this review, some examples of QS inhibitors like synthetic and natural based QS inhibitors are highlighted. This review is also focused on the inhibition of QS mechanisms and the application of QSI in various fields.

Quorum sensing, Inhibitors, Mechanism, Acyl homoserine lactones

INTRODUCTION: Antibiotics which discovered at the beginning of the twentieth century gave release for all human beings from various live threatening diseases ¹. But after the 20^th century, excessive use of antibiotics causes several problems like emergences of multiple drug-resistant bacterial strains ². About 16 million people died because of this infectious diseases ^{3, 4}. It is useful to mention that at least 65% of all these infectious diseases are linked to bacterial communities, which grow an enormous number by forming biofilms ⁵. It is seen that bacteria having special structure have high resistant power to antibiotics than planktonic counterparts ^{6, 7}.

In biofilms, quorum sensing control bacterial behavior and express intensive genes in a cell-dependent manner ^{8, 9, 10, 11}. If some efforts are applied to disrupt the biofilms, then it is easy to identify the molecules produced by eukaryotes and prokaryotes with ability to quench the QS system, known as quorum quenching (QQ) ^{3, 4, 12-21}. It can be noted that some synthetic compounds have very much effective power to regulate QS ^22-27.

Quorum Sensing (QS): Bacteria behave as social organisms that interact with each other and their surroundings, i.e. they can coordinate gene expression with their population density. This process is termed quorum sensing (QS) ²⁸. It is known as a cell density-dependent process (cell to cell communication) by which cells measure the population density and trigger proper responses ²⁹. Hastings et al., in 1977, reported the first QS phenomenon in the marine bacterium Vibrio fischeri ³⁰. Auto-inducers as specific signaling molecules play a vital role in QS and have three different classes based on their specific structures and functions. The main QS signal molecules are acyl-homoserine lactones, AIPs (auto-inducing peptides) ³¹. Gram-negative bacteria use AHLs as signaling molecules, and gram-positive bacteria produce AIPs as auto-inducers ³². Compounds with inhibiting power have been applied to preserve food, preventing biofilm growth and used for bacterial infections treatment. But when the growth of bacteria is blocked, they are in the high pressure to develop resistance. So we require to identify a suitable drug target ³³. QS enables bacteria to make collective decisions for a specific set of genes. Acyl homoserine lactones (AHLs) are the most signal molecules in gram-negative bacteria, synthesized by the LuxI homolog proteins ³⁴.

FIG. 1: BASIC STRUCTURE OF THE AHL SIGNAL MOLECULE WHERE R¹ = H, OH, OR O AND R² = C1–C18 ²⁸

Hypothetically AHL analogous may act as competitive inhibitors, and various QSIs were designed based upon this. In different species, the AHLs structures vary, but they have the main features of a lactonized homoserine ring and a hydrocarbon through amide bond ³⁵.

Synergism between QSIs and Antibiotics: There are a large number of bacteria that develop multiple drug resistance to antibiotics. The effect is best observed in the biofilms than the free-living counterparts ³⁶. It has been suggested that disrupt biofilms make the bacteria efficient even in low concentration of antibiotics ³⁷. The synergism between QSI and antibiotics is observed in Staphylococcus pathogenesis in which RNAIII-inhibiting peptide improve the clinically used antibiotics ^{38, 39, 40, 41, 42}. Ampicillin and baicalein antibiotics showed this synergism against P. aeruginosa ⁴³. Some QSI likes furanone C30, penicillic acid, and patulin increase the susceptibility of P. aeruginosa to tobramycin ^{4, 5, 44, 46}. Tobramycin (antibiotic) with baicalin hydrate (QSI) reduces the microbial population load in lungs ⁴⁷.

Examples of QS Inhibitors:

Synthetic QSIs: AHL scaffold is developed by three procedures: substitution and alternative introduction in the acyl side chain to maintain the lactone ring, substitutive and alternative introduction in the lactone ring to leave the acyl side chain unchanged and finally extensive modifications of both acyl side chain and lactone ring ²⁸.

Persson et al., created analogs able to block expression in both LuxR- and LasR-controlled QS reporters when he introduces sulfur in the acyl side chain instead of C-3 atom. Another QSI compounds are found in 3-oxo-C6 HSL/LuxR-controlled system by substitute the aryl group at the end of the side chain at least. The antagonistic effect is lost when the size of the substituent is increased beyond that of a phenyl group. Aryl compounds interact with aromatic amino acid residues in LuxR protein to prevent normal activation, if the difference in size of the aryl substituents and the cyclic alkyls is low ⁴⁸. Aryl AHLs become very effective as QSI when a sulphonyl group replaces the C-1 carbonyl group of the side chain ⁴⁹. AHL analogs interact with the receptor proteins, because of extra moieties on the C-3 ring atom. But they function as agonists ⁵⁰.

Natural QSIs: Plants and fungi are natural sources from which QSI compounds isolate. As QS bacteria have co-existed with both fungi and plants for many years, it may be expected that some of them produce compounds of QSI to reduce colonize of pathogenic capability, compete and transited bacteria ²⁸. There are a large number of organisms, which coexist in natural ecosystems. Bacteria can be communicated to co-operate among them and compete with others ⁵¹.

Prokaryotic QSI: Table 1 shows various organisms that produce QQ enzymes: (i) Actinobacteria- Streptomyces and Rhodococcus, (ii) Firmicutes- Bacillus, Arthrobacter, and Oceanobacillus (iii) Bacteroidetes -Tenacibaculum, (iv) Cyanobacteria - Anabaena, (v) Proteobacteria -Comomonas, Halomonas, P. aeruginosa, Ralstonia Acinetobacter, Variovorax paradaoxus, A. tumefaciens, Alteromonas, Klebsiella pneumonia, Hyphomonas and Stappia ^{16, 52-57}. Enzymes of four types decompose QS signals- AHL-lactonases, decarboxylases hydrolyze Lactone ring. But the acyl side chain is cleaved by AHL-acylase and deaminase. AHL- acylase present in P. aeruginosa (PAO1), Ralstonia sp. (XJ12B) Table 1 share identity around 39% at the level of amino acid ^{52, 58, 59}. Produce from Streptomyces sp., AHL-acylase degradation occurs at acyl chain having more than containing six carbon atoms. That is why it is specific ⁶⁰. B. subtilis, B. cereus, B. thuringiens is known as Bacillus spp. ^{54, 61, 62, 63, 64} produce AHL- lactones are sharing of 90% identity at their level of peptide ⁵² Table 2. AHL- lactones from A. tumefaciens share about 30-50% identity of their amino acid ⁵².

TABLE1: BACTERIAL ENZYMES AS QUORUM SENSING INHIBITORS ⁷⁴

Animal Based: Generally, in mice, rats, and zebrafish, QQ enzymes are found. Acylase was effective moderately to reduce the formation of biofilm by Pseudomonas putida and A. hydrophila ⁷⁵. Mammalian paraoxonas (PON), related to drug metabolism, detoxification to nerve agents enable hydrolytic activity on esters and lactones ^{52, 76}.

In mammals like a mouse, goat, bovine horse, and rabbit, QS signal- 3OC12HSL inactivate in serum ⁷⁷. Foods like turkey patties, breast of chicken, cheeses reduce 84–99% AI-2 activity ⁷⁸. Hall et al., designed PP7 virus-like particle and alleviated the animal’s infection ⁷⁹. Moutan Cortex disrupted the QS system of Pseudomonas fluorescens, which gave the freshness of fishery products ⁸⁰.

Plant-Based QSI: For similarities in chemical structure to QS signals (AHL) and the ability to degrade signal receptor (LasR/ LuxR), plant extracts can act as QSI ^{81, 82}. A promoter GABA (γ-aminobutyric acid) decompose AHL signal OHC8HSL by the lactonase of A. tumefaciens ⁸³. Pyrogallol from Emblica officinalis (medicinal plant), exhibits antagonistic property against AI-2 ⁸⁴. Curcuma longa, which produces curcumin inhibit P. aeruginosa ⁸⁵. Zhao et al. showed that the pharmaceutical composition of herbal organisms has the potential to treat bacterial infections with low resistance ⁸⁶.

Marine Organism Based QSI: Delisea pulchra produces halogenated furanone that inhibits QS mediated activity in bacteria. It is done when they compete with consanguineous AHL signal ^88-92. Bromoperoxidase enzymes may act like QSI to deactivate the signal of AHL (3OC6HSL) by oxidation ⁹³. In P. aeruginosa, 8 -epi-malygamide and malyngamide C are inhibited the QS activity ⁹⁴.

Fungus Based QSI: Secondary metabolites like antibiotics are produced by fungi Penicillium spp. which produced penicillin controlled bacterial infections ¹. Around 33 type Penicillium spp. will produced patulin and penicillin as QSI ⁴⁵. Fungi decompose association of C6HSL and 3OC6HSL with rhizosphere plant through lactonases activity ⁹⁵. Natural pigment from Auricularia auricular inhibits production of violacein in C. violaceum ⁹⁶.

Antibody-Based QSI: Among eukaryotes, antibodies generated from mammal’s immune system have a response to allergen ⁸¹.

TABLE2: QSI POTENTIAL OF THE TESTED PLANT EXTRACTS ⁸⁷

+: Moderate anti quorum sensing activity, ++: Potent anti quorum sensing activity

Antibody XYD-11G2 has the ability to degrade 3OC12HSL of P. aeruginosa ⁹⁷.

QS Inhibition Mechanism: Most of the QS inhibitors working principle is based on the following strategies: (a) QS signals degradation, (b) Biosynthesis of inhibited QS signal, (c) Detected QS signal inhibition, and (d) Antibiotics as QS inhibitors ⁹⁸.

FIG. 2: LAYOUT OF THE QSIS SCREENING SYSTEMS: (A) An AHL receptor/response regulator is activated by exogenously supplied AHL. The activated LuxR homolog (QS R) upregulates expression from a QS-regulated promoter (P Target) which controls the expression of a gene (killing gene) encoding a toxic protein leading to growth arrest or cell death. (B) If a QSI compound is present, the reception of the AHL signal is blocked, and expression of the killing gene is prevented, allowing for the growth of the screening bacterium ⁴.

QS Signals Degradation: QS signal may be degraded either by non-enzymatically or enzymatically. Three types of enzymes targeted the AHL signals. AHL-lactonase hydrolyzed the ester bond of the homoserine lactones ring in AHL^{53, 98}. Lactonase from the gene aiiA of Bacillus sp. 240B1 inactivate AHL ⁹⁹. QS Signals have been degraded by acylase that also degraded AHL and forms 3-oxodecanoic acid and homoserine lactone (HSL) ⁵⁹. The third class of enzyme named as oxidoreductase causes AHL degradation. The bpib09 enzyme can deactivate the 3-oxo C-12 homoserine lactone (3OC12HSL) ¹⁰⁰. Catalytic antibodies will also hydrolyze AHL signal ¹⁰¹.

Biosynthesis of Inhibited QS Signal: AHL production may be suppressed theoretically by one of the mechanism: acyl-ACP generation obstructing, SAM biosynthesis hampering, or inactivation of synthase enzyme ⁹⁸. Enzyme FabІ can catalyze the final step of biosynthesis of acyl-ACP, i.e., to provide acyl chain for biosynthesis of AHL ⁹⁸. Triclosan can lower the lactone production ¹⁰². MTAN will produced both AHL and AI-2 auto-inducers directly ⁹⁸. Anthranilate analog in P. aeruginosa may inhibit PQS production ¹⁰³. Recently, Ishii et al., examined that quench S. mutans QS can inhibit the peptidase activity of Com A cassettes ¹⁰⁴.

Detected QS Signal Inhibition: Non-productive signal-receptor complex inhibits the QS signal ⁹⁸. QS Probes are developed with the help of crystal structures that target LasR. Two isothiocyanate-based probes such as Іtc-11 and Іtc-12 covalently modify the nucleophilic cysteine-containing a ligand-binding pocket of LasR, and thereby inhibit QS ¹⁰⁵.

Antibiotics as QS Inhibitors: The alternative target behavior of antibiotics found in some species, are suggested by evidence ⁹⁸. There is an indication of the reduced expression of intensive P. aeruginosa factors, decreased making of exotoxin A, elastase, proteases, DNase, leukocidin, and phospholipase C without inhibiting the growing P. aeruginosa ^{98, 106, 107}.

QS Inhibitors from Endophytic Bacteria: There are many known bacteria which coordinate with each other’s behavior and interact through quorum sensing. Endophytic bacteria behave as biocontrol agents. The QQ activity of endophytic bacteria (Bacillus megaterium strain B4, Bacillus sp. strain B3, Bacillus sp. strain B11 and Brevibacillus borstelensis strain B8) unbounded from plant of Cannabis sativa L. are inquired by Kusari et al. ¹⁰⁰ Endophytic bacteria like Bacillus sp. will break up cell to cell QS signal in gram-negative Chromobacterium violaceum (DSM 30191) ¹⁰⁸. The endophytic B. amyloliquefaciens coming from poplar tree has its antagonist activity to B. dothidea ¹⁰⁹.

Biotechnological Applications:

Aquaculture: Aquaculture, a well establish food industry, is significantly affected by disease outbreaks ¹¹⁰. Brachionus plicatilis, which is valuable and indispensable as food, rotifer has its important for the aquaculture industry. Pathogens such as Vibrio sp., Aeromonas sp., and Pseudomonas sp. influence fish larvae and when used as feed cause detrimental effects ¹¹¹. Synthetic and natural brominated furanone has protected gnotobiotic sea shrimp from pathogenic of Artemia sanfranciscana. Vibrio spp. has a very effective application of QSI in the field of aquaculture. Kojic acid from Aspergillus sp. formless into non-toxic paint for regulating bacteria and diatoms has also been biotechnological application ¹¹². These will be preserved food and increase the safety of food ^{20, 113, 114}.

 Industrial Applications:

75. Waste Water Treatment: Membrane bioreactor is used as a wastewater treatment technology for reclamation and desalination of brackish. It will develop a pressure of transmembrane, caused permeability, and results costly in higher treatment ⁷⁵. A. hydrophila and P. putida form these types of biofilms ¹¹⁵.
76. Biotransformation: Like different molecules as QSIs, synthetic biology has better control over QS based bacterial biofilms without any external supervision. For chemical transformations, biofilms behave as important platforms in biorefineries. The disperser cells had 14% slower growth rate compared to the initial colonizers.

But they had ability than the planktonic cells to produce a 14-fold higher amount of the cognate QS signal molecule (3OC12HSL). E. coli, as an industrial workhorse, produce therapeutic proteins due to its rapid growth and high-yield of product ¹¹⁶. There is a risk of contamination of the biotransformation reactors, which lead to huge economic losses. It is based on the information that (i) E. coli can produce indole, and (ii) indole and its derivatives can reduce the virulence of P. aeruginosa, the impact of indole was evaluated in the mixed cultures ^{117, 118}.

Plant Cultivation: Epiphytic bacteria, the cognate QS signal molecule induced premature induction of QS expression. It resulted in the compression of swarming motility and disease on tobacco plants ^{119, 120}. For these unique characteristics, epiphytic bacteria has advantages for controlling diseases. M. testaceum, AHL-degrading bacterium which occurs naturally on the surface of potato leaf can protect the plant from bacterial pathogens like P. carotovorum, which causes soft rot disease ¹²¹.

Transgenic plants produced by introduction of lactonase into tobacco and potato plants and Aiia enzyme in E. carotovora reduced pathogenicity towards, tobacco, Chinese cabbage, cauliflower and potato plants ^{53, 62}. M. tranculata and Pisum sativum plants deflate QS mimics in response to bacterial infections ¹²².

Animals: Transgenic Drosophila harboring human paraoxonases 1 reduce the lethality induced by P. aeruginosa pathogen. It was seen that PON1 protect files from bacteria. Discovery of human–pathogen interaction through QQ studies provides therapeutic modalities for infection/inflammation and cardiovascular disease ¹²³.

Human Health: Adenosine plays an important role to regulate the secretion of electrolytes, regulate down of inflammation, disrupt epithelial cells to enable Bacillus anthracis and S. aureus to release phagocytic activity ¹²⁴. By repressing the iron acquisition, adenosine has an important role for bacterial growth ¹²⁵. QS Signal of P. aeruginosa (3-OC12HSL) is inhibited breast cancer cell lines of human body ¹²⁶. This has been proposed that synthetic AHL homologs may be exploited as QSIs ¹²⁷.

CONCLUSION: Our future finding will be the treating of the largest number of medicinal plants as a natural source of quorum sensing inhibitors which will control the unfavorable interaction of these QSIs with our human body. Nowadays, the QSIs are used as inhibitors basically on the basis of experimental observations with trial and error method. In this regard, if we employ the DFT calculations in association with other drug like parameters obtained from theoretical calculations on these QSIs, we will be able to synthesis more specific QSIs which will act as a better drug in a very short time and at low cost. This study has enlarged the scope of producing more specific and effective drugs for Quorum Sensing.

ACKNOWLEDGEMENT: The authors are grateful to the Departmental Special Assistance Scheme under the University Grants Commission, New Delhi and Head, all the members, Department of Chemistry, University of North Bengal, Darjeeling, India, for providing various facilities in connection with this review work.

CONFLICTS OF INTEREST: Authors declare that there is no potential conflicts of interest.

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     Sarkar K and Das RK: A review on quorum sensing inhibitors. Int J Pharm Sci & Res 2019; 10(12): 5224-33. doi: 10.13040/IJPSR.0975-8232.10(12).5224-33.

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