Keywords

1 Introduction

Infectious diseases are one of the major cause of mortality and morbidity. The development of multi antibiotic resistance among pathogenic bacteria has created immense clinical problem. Development of new antibacterial drugs with novel mechanism of action and use of new treatment strategies is urgently needed to combat the problem of infection caused by MDR-bacteria. Targeting virulence and pathogenicity is one of such strategy (Aqil et al. 2006).

Density dependent, small diffusible signal mediated gene regulation system in bacteria, that controls expression of virulence traits is termed as “Quorum sensing”. These small diffusible signal molecules or autoinducers allows bacteria to regulate expression of large sub-set of genes related to pathogenicity with change in bacterial population (Camara et al. 2002). This signalling system has distinct architecture necessary for signal dissemination, revelation and response and has been well characterized in Gram-negative and Gram-positive bacteria (Miller and Bassler 2001; Lazdunski et al. 2004). Dismantling QS networks without having toxicity on target bacteria is considered as one of the important alternative strategy for combating bacterial infections with advantageously decreasing the risk of selection pressure (Bjarnsholt and Givskov 2007; LaSarre and Federle 2013). Thus identification, characterization and development of effective quorum sensing inhibitors (QSI) considerably gain attention from scientific community worldwide as a promising remedy to combat infection caused by multi-resistance bacteria. A potential QSI would have act through three possible mechanisms, (a) targeting the signal generation, (b) degradation of signal molecule and/or by (c) blocking the signal receptors. A model QSI having potential to be transformed into successful anti-infective drug should be attributed with high target specificity and negative toxicity towards the target bacterium as well as the eukaryotic host (Rasmussen and Givskov 2006; Ahmad et al. 2011; Kalia 2013; LaSarre and Federle 2013).

Despite of remarkable development in combinatorial chemistry for providing wide range of lead molecules, naturally occurring plant products are still considered as preferred choice in pharmaceutical industry (Silva et al. 2016). Considering the extensive use of plants for medicinal and dietary purposes in human, efforts have been focussed towards plants and their derived products to explore potential therapeutic principles. Plants and their derived natural products represent a vast, unexplored and comparatively safe reservoirs of diverse bioactive compounds (Atanasov et al. 2015). These plant secondary metabolites spanning from simple phenols to highly diverse terpenes are involve in various biological process relating to plant defence against pathogens, assisting central metabolic processes, response against external stimulants etc. (Koh et al. 2013; Yarmolinsky et al. 2015). Interestingly, many plants products/phytochemicals offer entirely different mechanism of actions when compare to conventional antibacterial, representing an effective alternative to aging antibiotics (Cegelski et al. 2008; Nazzaro et al. 2013). Besides, plants derived natural products plays indispensable role in traditional medicine system worldwide including Chinese, Indian, and other folk medicine, thus research focussing plants derived products would help in bridging the gap between traditional wisdom and modern therapeutics (Adonizio et al. 2006; Ahmad et al. 2011; Zahin et al. 2010a). Role of medicinal plant products and phytocompounds against infectious agents and their diverse mode of action have been investigated and reviewed by several workers (Cowan 1999; Aqil et al. 2006; Palombo 2011; Husain and Ahmad 2013; Silva et al. 2016).

In this chapter, we present an update and brief review on anti QS activity of plants and its derived products including phytocompounds. We systematically covered plant derived natural products including plant extracts (crude or enriched), essential oils and phytocompounds, highlighting their anti-quorum sensing potential along with underlying their mechanism of actions. In the later sections, while addressing the significance of plant based QSI against infectious disease, an attempt have been made to highlight the development of successful plant based QSI that could possibly be used as anti-infective agent for management bacterial infections.

2 Plant Extracts with Anti QS Activity: A Recent Update

Studies in past have reported the ability of the plant extracts used in dietary or therapeutic purposes to interfere in intra and inter species QS communication. Plants are considered as vast reservoirs of bioactive chemicals and enzymes which could be act as natural quorum sensing inhibitors. The co-existence of bacteria and plant date back to millions of year which significantly results in the development and evolution of defensive mechanism against pathogenicity primarily involving the disruption of molecular communication. Among the natural strategies unfolded during past investigations includes enzymatic degradation of QS signals, the inhibition of autoinducer synthesis, receptor antagonism and disruption of signal secretion. However, recent advances in the field of plant based QSI research are more specifically focused on gene expression variation along with targeting global regulatory factors controlling overall QS mechanism. Table 20.1 shows list of common dietary and medicinal plants which have demonstrated QS inhibitory activity.

Table 20.1 Anti-QS activity of dietary and medicinal plants
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2.1 Dietary Plants

Recently, extracts of different botanical groups of dietary plant including fruits, vegetables and culinary herb and spices have been demonstrated as strong QSI (Table 20.1). Primarily, fruits received special attention, as they are important part of diet and exert beneficial effects on human health. Fruit extracts, owing to their rich dietary phytochemical content, have been recognized as promising source in the search of novel anti-infective (Truchado et al. 2015).

Aqueous extract of fruits of Ananas comosus (pineapple) and Manilkara zapota (sapodilla) were found to inhibit the QS system in Chromobacterium violaceum CV026 and P. aeruginosa PA01, inhibiting QS dependent virulence factors (pyocyanin, staphylolytic protease, elastase and biofilm formation) production (Musthafa et al. 2010). Apple extract when evaluated for QS inhibition against C. violaceum, showed a dose-dependent inhibition in pigment production (Fratianni et al. 2011). Koh and Tham (2011) showed that extract of Prunus armeniaca (apricot) inhibits AHL production in C. violaceum CV026 biosensor strain as well QS dependent swarming motility in P. aeruginosa PA01. Quorum sensing regulated production of AHLs and biofilm formation in Yersinia enterocolitica was found to be inhibited by flavonones rich orange extract (Truchado et al. 2012).

Berries are considered as rich source of phenolic phytochemicals such as flavonoids including anthocyanins, flavanols and flavonols, tannins, stilbenoids, phenolic acid and lignans (Vattem et al. 2007). It was observed that the production of AHL and AI-2 signal molecule was depleted under the influence of extracts of three berries when tested with C. violaceum CV026 and Vibrio harveyi BB170 tester strains and the effect was found to be concentration dependent. These phenolic rich extracts of raspberry and cloudberry also caused significant reduction of biofilm formation of Obesumbacterium proteus (Priha et al. 2014). Similarly, phenolic extracts of Rubus rosaefolius, a berry indigenous to Himalayan region of South Asia, inhibited all the phenotypes typically related to quorum sensing including violacein production, swarming motility and biofilm formation in C. violaceum, Aeromonas hydrophila and Serratia marcescens. Authors further observed that QS disruptive principle were predominantly natural phenols (Oliveira et al. 2016).

Another edible berry, Syzygium cumini, derived anthocyanin rich extracts examined for the anti-QS potential against different QS linked phenotypes in C. violaceum and Klebsiella pneumoniae. Anthocyanin constituent, malvidin, was found to interrupt the QS mechanism via binding with LasR regulatory protein as revealed from docking studies. Malvidin was also shown to inhibit virulence determinants e.g. biofilm formation and EPS (extracellular polymeric substances) production in K. pneumoniae (Gopu et al. 2015a). Phenolic rich extracts from Brazilian berries Eugenia brasiliensis and Eugenia uniflora have been confirmed for their quorum quenching capacities using C. violaceum biosensor strain (Rodrigues et al. 2016a, b). Moreover, the phenolic extract of grumixama (Eugenia brasiliensis) inhibited the QS regulated swarming motility in A. hydrophila and S. marcesens at concentration non-inhibitory to bacterial growth. Authors hypothesize that the observed QS inhibitory potential of the extract may have related to its phenolic constituents which have act synergistically or individually, producing the biological effect (Rodrigues et al. 2016a). Maisuria and co-workers (2016), evaluated the proanthocyanidins rich extract of cranberry (Vaccinium macrocarpon) against QS-linked virulence traits of P. aeruginosa in host Drosophila melanogaster. It was observed that application of the extract inhibited the production of virulence determinants and subsequently protected the host organism from fatal infection of P. aeruginosa. LC-MS analysis of culture supernatant revealed that levels of autoinducers (AHL) was depleted significantly. QS signalling genes including AHL synthesase LasI/RhlI and transcriptional regulators LasR/RhlR were also inhibited by proanthocyanidins rich extract. Additionally, in silico molecular modelling suggested that proanthocyanidins binds to QS transcriptional regulatory proteins, ultimately refraining the ligand molecules (autoinducers) to bind with active sites.

Herbs and spices are also considered as rich source of bioactive phytochemicals and extensively used in various food preparations as well as ethno-pharmaceuticals. Latest reports regarding biological activity prospect of these herbs and spices highlight their anti QS and anti-virulence potential (Table 20.1). Makhfian et al. (2015) screened 31 plant species including numerous spices and herbs for analysing their inhibitory potential against QS related behaviours, violacein pigment production in C. violaceum CV026 and plant tissue maceration caused by Pectobacterium carotovorum. Among them, the dill (Anethum graveolens) extract demonstrate AHL mimicking activity and subsequently inhibit violecein production to significant levels. Moreover, the extract was also effective against Pectobacterium carotovorum mediated tissue maceration in potato tubers and calla-lily slices. Trigonella foenum-graceum seed’s (commonly known as fenugreek) methanol extracts demonstrated inhibition of AHL regulated virulence factors e.g. protease, LasB, elastase, pyocyanin, chitinase, EPS and swarming motility in P. aeruginosa PA01 and PAF79 as well as QS regulated swarming motility in aquatic pathogen A. hydrophila WAF38. Further, the application of the bioactive extract subsequently downregulate lasB gene as evident from β-galactosidase luminescence in E. coli MG4/pKDT17. Additionally, in vivo infection model (Caenorhabditis elegans), the extract exhibit significant reduction in mortality rate in infected nematode. Caffeine was identified as a major volatile constituent in the extract, also showed significant reduction in QS regulated virulence traits including biofilm formation in pathogenic bacteria (Husain et al. 2015a).

Plant derived beverages including tea and coconut water have been also found to be effective against pathogenic bacteria via modulating their QS related response. Tea polyphenols interfered with autoinducers (AI-2 and diketopiperazines) activities of Shewanella baltica, promoted the degradation of AI-2 and was found to be function of epigallocatechin gallate constituent of the extract. Reduction in QS phenotypes such as biofilm development, swarming motility and exopolysaccharide production were suggested to be linked with downregulation of luxS and torA genes as revealed from transcriptional analysis (Zhu et al. 2015). Two-furaldehyde diethyl acetal (2FDA) was identified as potential QSI by screening of identified compounds from water of Coccus nucifera via molecular docking studies using transcriptional regulator proteins LasR and RhlR as target. Subsequent transcriptional analysis revealed down regulation of autoinducer genes (lasI/rhlI) and transcriptional regulator genes (lasR/rhlR) that corresponds to observed reduction in QS regulated traits including biofilm formation, aeruginolysin, LasA, LasB, elastase, protease, swarming motility, pigment and haemolysin production in P. aeruginosa. Authors also demonstrated the synergistic activity of palmitic acid, another bioactive constituent obtained from coconut water, increases overall QS inhibitory and anti-biofilm potential of 2-FDA (Sethupathy et al. 2015). Celery (Apium graveolens) leaf’s extract was found to inhibit pigment production in C. violaceum at significant levels, however other spices under the examination such as Syzygium anisatum, Glycyrrhiza glabra and Capsicum annuum showed moderate activity. The active constituent 3-n-butyl-4,5-dihydrophthalide (sedanenolide) was isolated from Apium graveolens extract and identified using preparative HPLC-MS followed by LC-ToF-MS analysis (Cosa et al. 2016).

2.2 Medicinal Plants

Apart from food plants, abundant accounts of quorum sensing inhibitory activity were also reported from medicinal plants. Ethnobotanical use of plants in treatment of various ailment including bacterial infection was one of the important convincing argument which scientific community put forward to direct the search of novel anti-infective or more precisely anti-QS agent from medicinal plants (Adonizio et al. 2006). With special reference to Indian medicinal plants, first attempt was made in 2006, screening the commonly used medicinal plants for their quorum sensing inhibitory properties (Sameena 2006). Subsequently, studies undertaken by several workers (Fatima et al. 2010; Musthafa et al. 2010; Harjai et al. 2010; Zahin et al. 2010b; Husain et al. 2013; Packiavathy et al. 2014; Tiwary et al. 2017), highlighted that Indian medicinal plants as a potential source of quorum sensing inhibitors.

Till date hundreds of medicinal plant extracts have been shown to exhibit anti-QS potential in one or more screening system (Kalia 2013; Yarmolinsky et al. 2015; Silva et al. 2016; Tiwary et al. 2017). The search of potential QSI from medicinal plants become more considerable keeping in view their long history of human use, thus toxicity issues, at least hypothetically, can be ruled out. Furthermore, this search will also boost the concept of evidence based complementary medicine and shed new light on important biological mechanism through which these plant based non-conventional remedy system works (Kothari et al. 2017). Development of medicinal plants into successful anti-pathogenic alternative will also eliminate the present day’s shortcomings with conventional antibiotics including development of resistance apart from other side-effects.

As discussed in earlier sections, owing to their rich, diverse and continuously evolving bioactive chemical source, these plants are considered to most effective and most important candidate therapeutics. Table 20.1 presents a brief account of recent reports concerning quorum sensing modulatory effect of various medicinal plant extracts.

2.3 Essential Oils

Essential oil derived from plants are widely been recognised as flavouring agent and antimicrobials. Their biological efficacy has been attributed to their constiuent phenolics, terpenes and terpenoid volatiles (Bakkali et al. 2008). These essential oils have also been reported to possess anti-QS properties (Khan et al. 2009; Szabó et al. 2010). Table 20.2 summaries some of the recent reports on QS inhibiting potential of essential oils.

Table 20.2 Anti-QS activity of essential oils
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Khan et al. (2009) screened 21 commonly used essential using biosensor strains, C. violaceum CV12472 and CVO26. Among them, four essential oils, clove, cinnamon, lavender and peppermint oil showed varying level of QS inhibitory effects in a dose dependent manner. Yap and co-workers (2014) highlight the role of QS inhibitory and membrane disruption action of lavender (Lavandula angustifolia) oil as possible mechanism for the observed antibacterial effects. The oil was assayed employing two bioluminescence biosensor strains Escherichia coli [pSB1075] and E. coli [pSB401] and found effective against the LasR receptor containing strain E. coli [pSB1075]. While evaluating different chemotype of essential oil obtained from Lippia alba, Olivero-Verbel and co-worker (2014) observed that oil containing high ratio of geranial:neral and limonene:carvone were found to be most effective against QS-controlled violacein pigment production. Moreover, among the two, geranial/neral chemotype was also found effective against Staphylococcus aureus. Sub-lethal concentrations of cinnamon oil were found reduce the production of both short and long chain AHL molecules as evident from CV026 and PA01 bioassay. Subsequently, the lower levels of AHL signals were also found in relationship with observed inhibition of pyocyanin, swarming motility, alginate and total exoprotease activity in PA01. Authors suggested that cinnamaldeyde, a major volatile constituent of cinnamon oil could be responsible for observed anti QS activity, nonetheless, other constituent such as eugenol may synergistically or solitary targeted the QS circuit in the tested bacterium (Kalia et al. 2015).

Coriander essential and its major constituent were shown to significantly inhibit the biofilm formation in Campylobacter jejuni and Campylobacter coli. The oil and its major component linalool also demonstrate inhibitory effects against the production of QS-controlled violecein pigment in C. violaceum biosensor strains. Authors concluded that observed anti biofilm activity against the food borne pathogen could possibly the outcome of quorum sensing disruption (Duarte et al. 2016). Luis and co-workers (2016) evaluate anti-QS properties of two eucalypt essential oils namely E. radiata and E. globulus containing limonene and eucalyptol as major constituent respectively. E. Radiate was shown to exhibit greater QS interfering potential. Citrus reticulate essential oils and limonene, a cyclic monoterpene, have been shown to decrease the autoinducer (AHL) reduction levels by 33% as evident from P. aeruginosa qsc 119 bioreporter strain, and subsequently decreasing the elastase enzyme in P. aeruginosa HT5 by 75%. However, authors suggested, as revealed by the relationship between elastase production and AHL inhibition, that overall reduction in enzymatic activity was not only due to QS disruption, but also because of direct inhibitory effect of essential oils and its component on the enzyme activity (Luciardi et al. 2016). Pratiwi et al. (2016), while investigating the quorum quenching effect of Cryptocaria massoia essential oil observed that the oil effectively impeded the QS-dependent swarming motility of P. aeruginosa PA01 and violacein reduction in C. violaceum CV026 biosensor. Similarly, Ferula asafoetida and Dorema aucheri essential oil have also been found to be active against P. aeruginosa associated virulence factors including pyoverdine, pyocyanin, elastase and biofilm at significantly low concentration (25 μg/ml). Homoserin lactones (HSL) inhibition and down regulation of QS related genes were considered as apparent mode of action of the oils as observed from in vitro assessments. Additionally, keeping in view the diverse of chemical composition of the oil, authors speculated that multiple QS associated molecular target might be affected or global regulator like Vfr or GacA might be impeded (Sepahi et al. 2015). Bai and Vittal (2014) and Ganesh and Rai (2016), independently evaluated the quorum sensing inhibitory activity of essential oil of Murraya koenigii and found to be active against AHL mediated cell communication. Biofilm formation, cell attachment, EPS production and biofilm maturation by P. aeruginosa were shown to be attenuated at sub-MICs of the oil. Food spoilage by psychotropic P. psychrophila PSPF19 was also found to be delayed under the influence of the oil and related to its observed anti-QS activity (Bai and Vittal 2014). Ganesh and Rai (2016) examined the antipathogenic efficacy of Murraya koenigii essential oil in vivo using nematode C. elegans–Pseudomonas aeruginosa infection model. Along with rescuing 60% of C. elegans, the oil was also shown to inhibit other virulence factors such as pyocyanin and LasA staphylotic activity significantly. Asghar et al. (2017), demonstrated the activity of Elletaria cardamomum (zingiberaceae) essential oil against the pigment production in C. violaceum at the concentrations non-inhibitory to bacterial growth. Authors suggested that volatile components of the oil such as α-terpinyl acetate, 1,8-cineole, linalool acetate etc., could be responsible for the observed biological effect.

3 Plant Derived Phytocompounds as QSI

Different plant based chemical molecules comprising of diverse chemical groups including flavonoids, fatty acid derivatives, alkaloids, coumarins, lignans, terpenoids etc., have been identified as potent anti-quorum sensing agent (Nazzaro et al. 2013; Silva et al. 2016; Asfour 2017). Recent reports on bioactive photochemicals against QS mechanism and chemical structures has been presented in Table 20.3 and Fig. 20.1. A brief description of some of important chemical groups is presented as follows.

Table 20.3 Anti-QS activity and mode of actions of plant derived phytocompounds
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Fig. 20.1
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Chemical structures of some of the plant derived QSIs

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3.1 Flavonoids

Flavonoid, a widely distributed plant secondary metabolites known for their antioxidant and antibacterial efficacy primarily engaged in root elongation process of various plants. These polyphenolic compounds having characteristic benzo-ϒ-pyrene ring are synthesised via phenylproponoid pathway (Kumar and Pandey 2013). Among other pharmacological potentials, this class of plant secondary metabolites have also been shown to possess anti-virulence and anti-QS properties (Paczkowski et al. 2017).

O-glycosylated flavonoids isolated from orange peel including naringin, neohesperidin and hesperidin showed anti QS capacity in C. violaceum biosensor strain. These flavonoids were also shown to inhibit QS mediated virulence factors in human enteropathogen Y. enterocolitica by decreasing the expression of different genes involves in virulence production (Truchado et al. 2012). Brango-Vanegas et al. (2014) identified numerous flavonoids from Cecropia pachystachya Trécul, a widely distributed medicinal plant in Latin America. These C-glycosyl flavonoids such as chlorogenic acid, isoorientin, orientin, isovitexin, vitexin and rutin were shown to act as QS antagonist when screened against C. violaceum ATCC 31532 and E. coli pSB403 biosensor strains. Two structurally related flavonoids first time isolated from Piper delineatum were shown to downregulates the QS regulated bioluminescence in V. harveyi reporter strain. These flavonoids broadly classified into methoxy flavones and methoxychalcones groups targets downstream LuxO component in V. harveyi at significantly low concentration without affecting the bacterial growth (Martín-Rodríguez et al. 2015). Baicalein (5,6,7-trihydroxyflavone) was shown to reduce the levels of enterotoxin A (SEA) and α-hemolysin (hla) in clinical strain of biofilm forming S. aureus (Chen et al. 2016). Notably, baicalein treatment significantly downregulated the quorum sensing regulators agrA, RNAlll and sarA as well as expression of ica gene at sub-inhibitory concentrations (32 and 64 μg/ml). Conformational changes in 3D structure of LasR protein of K. Pneumonia was evident on binding with petunidin (flavonoid) and demonstrated using simulation studies (Gopu et al. 2016). Root Mean Square Deviation (RMSD) value of thermal dynamism representing the deviation of 3D structure of LasR–OHL and LasR–petunidin complexes revealed that interaction with petunidin results into closing of active sites of the receptor protein and its further interaction which would otherwise remain open when OHL (auto inducer) molecule was present. The structural activity relationship analysis of different flavonoids reveals that the presence of two hydroxyl groups in the flavone A ring are essential for inhibition of QS related self-regulatory proteins in P. aeruginosa. Biochemically it was also established that flavonoids prevent LasR/RhlR-DNA binding non-competitively (Paczkowski et al. 2017). Quercitin, a ubiquitous flavonoids, binds to QS receptor protein LasR and reduce their ability to bind promoter region of DNA thus by down regulating overall expression of QS related genes. Further, Paczkowski et al. (2017) and Gopu et al. (2015b) independently demonstrated that binding of quercetin to receptor protein of P. aeruginosa results into conformational changes in the protein structure.

3.2 Other Phenolics

Other bioactive phenolic secondary metabolites such as phenolic acids blocks the expression of virulence factors in pathogenic bacterium via modulating QS machinery (Truchado et al. 2012). Truchado and co-workers (2012) evaluated the potential of several food phytochemicals to inhibit QS signals in the biosensor strain C. violaceum. A preliminary screening using three different concentrations showed that gallic acid and vanilic acid reduced violacein through QS inhibition. Borges and co-workers (2014) also observed the QSI potential of gallic acid, which inhibited pigment production, although all concentrations tested were cytotoxic to mouse lung fibroblasts. Anti QS properties of coumarin, another polyphenolic compound belongs to benzopyrene class, in three biosensor strains (S. marcescens, for short chain AHLs, C. violaceum for medium chain AHLs and A. tumefaciens for long chain AHLs) was analysed by Gutiérrez-Barranquero et al. (2015). The compound showed varying level of inhibitory activity against different AHLs and downregulated the expression of QS controlled genes pqsA and rhlI.

The ability of rosmarinic acid, a phenolic acid predominantly found in members of Lamiaceae family was tested in different pathogenic strains of A. hydrophila isolated from infected zebra fish. Rosmarinic acid influenced QS regulated virulence factors such as biofilm formation, haemolysin, lipase and elastase production. Gene expression analysis confirmed the down regulation of virulence genes such as ahh1, aerA etc. It was also observed that in vivo treatment of rosmarinic acid in zebra fish infection model subsequently enhances the survival rate (Rama Devi et al. 2016). Tannic acid significantly downregulates Ahyl and AhyR transcript in the tested bacterium as revealed from qRT-PCR results. The phenolic compounds were also tested in Catla catla when co-stimulated with pathogenic bacterium (A. hydrophila) and shown to decline the extent of pathogen induced skin haemorrhage and enhanced the survival rate up to 86.6% (Patel et al. 2017). Ilic-Tomic and co-workers (2017), examined the QS inhibitory effect of diarylheptanoids isolated from barks of Alnus viridis, it was demonstrated that among the isolated diarylheptanoids, hirsutenone was able to inhibit the QS dependent pigment production in C. violaceum CV026 and P. aeruginosa PA01 along with reduction in the levels of the auto inducer molecule (2-alkyl-4-quinolones) in P. aeruginosa PA01.

Among the plant derived pigments, zeaxathin was screened for potential QS inhibitory activity using two lasB-gfp and rhlA-gfp fluorescent monitor strains of P. aeruginosa. Gene expression levels of lasB and rhlA was observed to decrease in concentration dependent manner. Further, In silico modelling approach revealed the significantly favourable stabilizing binding energy of zeaxathin with the active sites of lasB and rhlA. Authors thus suggested that the potential QSI (zeaxathin) imparts its effect via inhibition of regulatory proteins involves in QS circuit (Gökalsın et al. 2017).

3.3 Essential Oil’s Compounds

Essential oil’s compounds, primarily mono-terpenes and sesquiterpenes have been primarily screened for their anti-QS potential against C. violaceum and P. aeruginosa PA01 bioreporter strains (Ahmad et al. 2015). It was revealed that stereochemical variations among the structurally similar components could be responsible for obtained activity. It has been shown (+)-enantiomers of carvone, limonene and borneol increased violacein and pyocyanin production, on the contrary levo (−) analogs such as a-terpineol and cis-3-nonen-1-ol showed more that 90% inhibition in the pigment production. It was also emphasized that mimicking the autoinducer signals structurally could be considered as possible mechanism of action in virulence inhibition (Ahmad et al. 2015). Two important pungent constituents of ginger oil, 6-gingerol and zingerone were also been investigated to evaluate their ability to interfere with QS and regulated traits in P. aeruginosa (Kim et al. 2015; Kumar et al. 2015). Kim et al. (2015) observed that application of 6-gingerol successfully reduced QS regulated virulence factors such as exoprotease, rhamnolipid, biofilm formation etc., in the target bacterium. In-silico analysis suggested that the test molecule interfere with the active sites of QS receptor protein lasR via multiple weak interactions. Authors also observed the reduction in QS-induced genes expression under the effect of 6-gingerol thus by confirming the role of 6-gingerol at molecular levels interfering the QS system. Kumar and co-workers (2015), virtually examined the interaction of zingerone with different QS receptors (TraR, LasR, RhlR and PqsR) and observed comparative good docking score to respective autoinducer, thus by proposing zingerone as a promising anti-infective drug candidate. Menthol (5-Methyl-2-(propan-2-yl)cyclohexan-1-ol) has been putatively identified as potent QSI among other component of peppermint oil using molecular docking technique. Further in vitro assessments reveals that menthol significantly reduces expression of QS-controlled traits at sub-MICs in C. violaceum and P. aeruginosa PA01 in a concentration dependent manner. The addition of menthol to E. coli biosensors, MG4/pKDT17 and pEAL08-2 reduced the β-galactosidase luminescence indicating the direct inhibition of las and pqs transcription respectively (Husain et al. 2015b). Carvacrol and thymol a monoterpenoid phenol was described to inhibit the QS evidently through inhibiting the production of signal molecules (Myszka et al. 2016; Tapia-Rodriguez et al. 2017). In Pseudomonas fluorescens KM121biosensor system, carvacrol and thymol were examined for their ability to interfere the production of quorum sensing autoinducers (AHLs) and flagellar gene (flgA) expression. Both the components (carvacrol and thymol) of Thymus vulgare essential oil significantly modulates the levels of AHLs along with downregulating the expression of motility (flagellar) genes at sub-MIC concentrations (Myszka et al. 2016). Al-Shabib and co-workers (2016), showed that eugenol significantly inhibited the QS regulated violecin production in C. violaceum CV026 along with virulence factors in P. aeruginosa PA01. Additionally transcriptional regulation assay in E. coli MG4/pKDT17 indicates that observed anti QS activity of eugenol is associated with downregulation of las system. Inhibition of QS-controlled production of prodigiosin pigment in S. marcescens was observed when treated with sub-inhibitory concentrations of phytol, an acyclic diterpene alcohol isolated from Piper betle (Srinivasan et al. 2016). Other related virulence traits including biofilm, hydrophobicity and protease production were also shown to reduce significantly at non-toxic concentration of the volatile component. Alves et al. (2016) screened major components of essential oil of Coriandrum sativum including linalool, α-pinene, p-cymene, camphor and geranyl acetate. It was observed that linalool exhibits significant inhibition in the pigment production in C. violaceum and QS-dependent bacterial adhesion and biofilm formation in Acinetobacter baumannii without affecting the growth of test bacterium.

4 Significance of Plant Based QSIs in Combating Bacterial Infection

Development of plant based QSI which can be successfully used as an anti-infective is considered as an ultimate health benefit (Fig. 20.2). Numerous potential plant derived products and synthetic QSIs have been evaluated in animal models (Rumbaugh et al. 1999; Christensen et al. 2007; Nidadavolu et al. 2012). Various animal based in vivo models mimicking actual disease conditions like dermonecrosis, lung infection, wound infection, device associated infection and biofilm formation have been developed to test the efficacy of candidate QSI for their possible use in human subjects (Papaioannou et al. 2013). Alternatively, these models can be used for validating the use of plants based alternative medicine and substantiate their efficacy with scientific proof. In a study involving mouse infection model and human cell lines, Muhs and co-workers (2017), demonstrate the skin infection treatment ability of S. terebinthifolia, an exotic South American weed used locally for treatment of skin infection. The flavone rich active fraction obtained from the plant was shown to possess anti-virulence ability against S. aureus via modulating the bacterial agr quorum sensing system. The fraction was shown to be well tolerated by human keratinocytes in cell culture and mouse skin in vivo. The fraction also inhibited virulent MRSA mediated dermonecrosis in mouse skin model. Baicalin, one of the major flavonoid isolated from roots Scutellaria baicalensis have been shown to strengthen the immune response against P. aeruginosa infection in mouse model. During preliminary investigation, baicalin was evaluated against different virulence factors including biofilm formation in P. aeruginosa and was found be effective in a concentration dependent manner. The authors further observed QSI application results in overall improvement in immune response which was marked by the decrease in interleukin (IL-4) levels, increase in interferon (IFN-ϒ) and reversing interlukin/interferon ratio thus by activating Th-1 induced immune response in the infected host (Luo et al. 2017). Ruffin et al. (2016), observed that LasB and LasA protease secreted by P. aeruginosa in airways of patients with CF or other lung disease could further hamper the ability of epithelia to repair. Authors demonstrated that, furaneol, a known QSI isolated from Fragaria ananassa impeded the LasR transcriptional regulators thereby inhibiting the production of elastase in P. aeruginosa cultures. Further, they confirmed the effect of the QSI in patients with CF, a dose dependent wound healing response was observed following the application of the candidate QSI.

Fig. 20.2
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Applications of plant based QSIs in combating bacterial infections

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Another important aspects of QSI affecting the human health involves the possible effect of QSI on the dynamics of microbial community in human gut (McCarthy and O’Gara 2015). It has been well established microbial community in human body produce signalling molecules including AHLs (Yin et al. 2012; Swearingen et al. 2013). Thus inhibitory effect of QSIs on these microbial community is highly probable. However, this possibility and the outcome yet to be studied in human. Dietary phytochemicals exhibiting anti-QS or more specifically signal degrading activity could modulate the signalling system in commensal microbial communities. As these microbial communities are also responsible for host metabolic condition such as diabetes and obesity (Hur and Lee 2015), the shift in microbial profile under the effect of dietary QSI or as therapeutic is likely to be more possible. Thus understanding and gaining deep view of interconnection between QSI and gut microbial flora would clearly enhance our understanding of population dynamics, and their role in development of specific metabolic condition. The influence of dietary substances on microbial signalling within human host may also have medicinal impact (McCarthy and O’Gara 2015). Future work on the determining the interaction between QSI and human microbiome and their possible outcome will open entirely new arena of disease management. The development of pharmaceuticals, nutraceuticals and functional food with their possible role in modulating over all human microbiome will not only substantiate our battle against bacterial infection but also proved to be effective against other pathophysiological conditions.

5 Conclusion

Bacterial pathogenicity is a multifactorial phenomenon involving complex process of host-pathogen interaction. The degree of the pathogenicity is controlled through various cell structures and extracellular products called virulence factors. Expression of various virulence factors are known to be regulated through Quorum sensing. It is expected that attenuating virulence through QS interference in pathogenic bacteria may successfully result in disease control especially where antibiotic is ineffective due development of multi drug resistance. The literature survey in this article revealed that several plant derived products and phytocompounds can be considered as promising candidate for anti-infective drug development. However, further evaluation of these compounds using in vivo infection model for their proved therapeutic effectiveness are needed. To exploit anti-QS strategy in the control of bacterial infections, what is more challenging is to obtain active compound or formulation effective against number of QS network present in pathogenic bacteria to attenuate its virulence effectively, so that host defence system can clear the infectious agent.

6 Opinion

Considering the current global scenario of emergence and spread of MDR pathogens and slow discovery of new antibiotics with novel mode of action, it is necessary to develop alternative mode of bacterial infection control. The progress made so far on the role of QSI in the treatment of bacterial infection still weak and clumsy. Therefore, more concerted efforts should be directed to understand the linkage of various virulence factors with QS and how to effectively target virulence of pathogen through QS inhibition as well as use of other strategy in combination with QSIs.