Bioactive compounds from marine algae and fungi in down-regulating quorum sensing

Abstract

The prevalence of antibiotic resistance in a broad range of clinically significant microorganisms has been consistently increasing. This prevalent problem is one of the main challenges of the twenty-first century. Quorum sensing inhibitors (QSi) or quorum quenching render a potential substitute or potent adjuvants of conventional antibiotics for the treatment of antibiotic-resistant bacterial strains since these substances may reduce the pathogenicity of bacteria without levying the selection pressure associated with antibacterial therapies. In the marine environment, poisonous and beneficial bacteria cohabit alongside eukaryotes including algae, and fungus. Consequently, it is not surprising that eukaryotes have developed a range of defense mechanisms for interacting with bacteria, including the synthesis of secondary metabolites. The bioactive compounds derived from green, red, and brown algae and fungi like epicoccum, penicillum, furasium, and many more have demonstrated quorum inhibition properties against different microbial including pathogenic species such as Bacillus sp., Mycobacterium tuberculosis, Agrobacterium tumefaciens, Variovorax sp., Vibrio fischeri. Chromobacterium violaceum and ESKAPE pathogens. However, in gram-negative bacteria, the two proteins that compose up quorum sensing (QS) systems are the AHL synthetase, also known as the LuxI-homologue, which generates the AHL signal, and the LuxR homolog, a dual-function receptor response protein that binds and recognizes AHL molecules to facilitate interactions with quorum sensing controlled promoter sequences. This study focuses on several bioactive compounds derived from marine microorganisms, particularly fungi and algae that have been found to possess inhibitory effects on quorum sensing including the underlying mechanism of quorum sensing.

Introduction

Antibiotic mistreat and negligence have led to drug-resistant microorganisms. Using QS, biofilm-based bacteria produce the most contagious illnesses [77]. Antibiotic misuse and negligence have led to drug-resistant microorganisms. Using QS, biofilm-based bacteria produce the most contagious illnesses [66, 68, 131]. QS helps bacteria negotiate with each other and adapt to changes in population size and environmental makeup. External signaling molecules called autoinducers help bacteria coordinate gene expression. Certain receptors in the cytoplasm or cell membrane may identify these autoinducers after release [18, 142]. When autoinducers reach a threshold concentration, a signal cascade triggers bacterial gene expression, bioluminescence, virulence factor release, biofilm growth, and other biological functions. Gram-negative bacteria produce N-acyl-homoserine lactones (AHLs) with partner LuxI-type synthases, which LuxR-type QS receptors detect. Gram-negative bacteria mostly use AHLs as QS autoinducers. Pseudomonas quinolone signal, autoinducer-2, diffusible signal factor, and new chemicals also diverge from this pattern [40, 99, 100]. Most Gram-negative bacteria use AHLs as quorum-sensing autoinducers. Unlike LuxI/R homologs, gram-positive bacteria autoinduce using unmodified or modified oligopeptides. The cell and inner membrane sensor kinase are connected to various autoinducers. When peptides engage with this kinase and phosphatase, they change the phosphorylation of bacterial cognate response regulators, which stimulates or inhibits QS target genes [76]. QSIs are present in marine bacteria, actinomycetes, and fungi. Algae also contain bioactive compounds. Marine algae species with bioactive substances like flavonoids, fatty acids, complex carbohydrates, amino acids, and tocopherols are used in food supplements, cosmetics, medications, and cosmetics due to their high value [18, 86, 118].

Vegetation foliage, outer covering, reproductive structures, and biological catalysts produced by fungi and bacteria. In recent years, several bioactive compounds derived from marine algae have been discovered as effective solutions in the search for alternative medications to combat diseases with QS and multidrug resistance. Researchers have recently been focused on identifying specific seaweeds that produce biological chemicals with anti-QS properties. As a result, there is a growing interest among researchers in exploring the bioactive components of macroalgae as a source of anti-QS molecules [7, 10, 87, 110]. Marine algal species such as Isochrysis galbana, Phaeodactylum tricornutum, Skeletonema costatum, Chlorella vulgaris, Fishcerella species, Lyngbya majuscule, Chlorococcum species, Dunaliella salina, Amphidinium species, Navicula delognei, Haslea ostreasria, Chlorococcum HS-101, Phaeocystis species contains different metabolites such as carotenoids, Ppycobiliproteins, chlorophyll A derivative, diterpenoids, eicosapentaenoic acid, Unsaturated, saturated long chain, fatty acids, chlorellin, ambiguine isonitrile, haplindol T, malyngolide, Β-ionone, neophytadiene, amphidinolide Q, karatungiols, transphytol ester, mareninne, α-Linolenic acid, acrylic acid which QSi properties against bacterial species [3]. Due to their richness, marine microbial species have long been regarded as a possible source of new chemical compounds with various biological effects. However, marine microbial genera have not been fully used like terrestrial ones [6]. QS appears to be common in marine aquatic habitats. In marine environments [60]. For instance, Halobacillus salinus' abundant secondary metabolites impede bacterial quorum sensing. The study tested 332 g-positive isolates from maritime habitats for their capacity to block Vibrio harveyi's bioluminescence, which regulates cell signaling. Bioluminescence was suppressed by 49 bacteria strains and 28 of their metabolite extracts in V. harveyi. [125]. Signal molecule receptor sites, modulating chemicals, and QS suppression are the main targets. Bioactive components in many natural compounds decrease quorum sensing. QQ reduces biofilm development and multidrug-resistant pathogen growth in gram-negative bacterial infections [7]. Blocking the QS system, which gram-negative and gram-positive bacteria use, may treat bacterial infections [71, 95]. QSIs disrupt gram-negative bacteria's QS system in several ways. These strategies involve (a) inhibiting autoinducer synthases or receptor proteins, (b) inhibiting autoinducer production, (c) breaking down autoinducers, and (d) competing with autoinducer and protein receptor analogs to disrupt autoinducer and receptor binding to proteins [38]. Therefore, this review offers an in-depth exploration of marine algae and fungus-derived bioactive compounds (Fig. 1) in QSI activity including their possible effect on microbes including ESKAPE pathogens.

Fig. 1

Bioactive substance from marine algae and fungus in QSI

Bioactive compounds: a potentially plentiful source from marine algae and fungus

Secondary metabolic products comprising alkaloids, polyketides, terpenoids, isoprenoids, and quinines are abundant in marine fungi in association with algae, animals, sponges, and sediments [54]. Bioactive chemicals for QSI may be obtained from a variety of source algae and fungal organisms (Fig. 2) [53]. These organisms are commonly categorized into two groups: facultative and obligatory marine fungi. This difference remains disputed in terms of diversity and ecological relevance [26]. The concept of marine fungus has been rendered unclear by oversimplified statements. The fact that marine fungi may grow in a range of marine environments, such as salt marshes, hydrothermal regions, and even the depths of the ocean, is often overlooked [49]. Fungi have been identified shown to be prevalent in almost all maritime ecosystems, encompassing sediments [4], the marine water column [143], and amalgamations with sponges, corals, and algae [25, 46, 52, 149]. Marine fungi are present in both deep and near-surface waters and are a dependable source of several bioactive compounds [26].

Fig. 2

Potential source of QSIs from marine fungi and algae

Ascomycetous fungi are the subject of the majority of studies for QSI activity. The QS hindering the action of compounds from coral reefs belonging to the genera Epicoccum, Fusarium, Huskia, and Sarocladium was observed in C. violaceum CVO26 [83]. Kojic acid was isolated from Altenaria sp., which is associated with Ulva pertusa, a green alga. [79]. The compound was shown in a subsequent investigation to be capable of suppressing bioluminescence in E. coli pSB401 and violacein synthesis in C. violaceum CV017. Numerous bioactive chemicals, including QSIs, have been discovered to be produced by marine algae [6]. For instance, research has examined how several microalgae strains affect the AHL-regulated QS in V. harveyi and C. violaceum CV026. The study reaveled that, AHL-regulated pigment synthesis in the strain C. violaceum CV026 has been observed to be suppressed by C. saccharophila CCAP211/48 and C. vulgaris CCAP211/12. The marine-associated algae such as T. suecica CCAP66/4, Nannochloropsis CCAP849/9, T. striata SAG41.85, Isochrysis sp. CCAP927/14, and T. tetrathele SAG161-2 C have been substantially inhibited QS-regulated green fluorescent protein (GFP) production in E. coli JB523 strain. In addition, C. saccharophila CCAP211/48 consistently inhibited AHL-regulated luminescence in V. harveyi during two hours of incubation period, suggesting that this algae produces antagonistic metabolites like halogenated furanones [82] as well as a combination of isethionic acid, betonicine, and floridoside [78, 89]. Additionally, QS in C. violaceum CV017 was hindered by meleagrin, a molecule derived from Penicillum chrysogonium [29]. A recent research identified six QSIs from Penicillium sp. SCS-KFD08, including aculene C-E, penicitor B, and aspergillumarin A and B. The generation of these substances was likewise decreased in C. violaceum CV026 [75].

Extracted materials from the green microalga Chlorella saccharophila CCAP211/48 specifically prevented CV026 from producing violacein and hampered V. harveyi's ability to produce bioluminescence without changing cell densities. Chlamydomonas reinhardtii, a green microalga, has been found to hinder AHL-mediated luminescence. The study revealed that the levels of QSIs in algae grown through photosynthesis were significantly higher compared to those in cultures supplemented with acetate [127]. Halogenated furanones produced by the marine red macroalga Delisea pulchra are known to inhibit AHL-mediated QS. It is quite likely that these halogenated furanones linked to LuxR-type proteins because they have structural similarities with AHLs [81]. AHL antagonists are also produced by Ahnfeltiopsis flabelliformes, a red macroalga. Three compounds namely floridoside, betonicine, and isethionic acid were identified after bioactivity-guided fractionation [73]. Subsequent research additionally assessed the efficacy of chemically synthesized floridoside, betonicine, and commercially available isethionic acid, both singly and in combination [78]. The combination of floridoside and isethionic acid effectively and effectively inhibited QS. Another maritime red macroalgae, Asparagopsis taxiformis, showed QSI activity towards Serratia liquefaciens MG44 and C. violaceum (CV026). The active substance of the investigation has been discovered to be 2-dodecanoyloxyethanesulfonate [64]. Sargassum muticum extract was shown to suppress QS in the reporter C. violaceum CV017 in a recent study. The diatom Closterium cylindrotheca and bryozoan larvae (Bugula neritina) were both effectively inhibited by the crude extract's antifouling properties [115].

Neosartorya, a species of fungi found in marine environments, is closely related to the A. fumigatus group based on their phylogenetic relationship. It may be inferred from this that Aspergillus species and Neosartorya fungus generate comparable secondary metabolites. It has been found that the secondary metabolites of Aspergillus and Neosartorya exhibit numerous common characteristics, especially those related to indoles, meroterpenoids, and polyketides. Additionally, they have discovered that, depending on the habitat in which they are located, the same species can have several types of metabolites. Prenylated indoles, 1,4-benzodiazepen-2,5-dione-containing prenylated indoles, indole alkaloids, and several additional substances including peptides, terpenoids, sterols, polyketides, derivatives of benzoic acid, and nucleosides are among them. The biological and therapeutic effects of substances identified from members of the Neosartorya genus were primarily investigated in vitro. Most of the naturally occurring compounds derived from Neosartorya species have anticancer, cytotoxic, and antibacterial activities that are indistinguishable from those of other natural substances [25].

QS: an approach that regulates bacterial genes' expression

Small signal molecules are used in QS, a mechanism that controls the expression of certain genes. Vibrio fischeri is the organism that originally revealed this process [90]. QS encompasses three main steps: (i) the synthesis of extracellular signaling molecules known as autoinducers, (ii) the recognition of these molecules by bacterial communities, and (iii) the triggering of suitable reactions. QS systems are recognized for regulating a wide range of functions, including bioluminescence, biofilm formation, conjugation, antibiotic synthesis, nodulation, swarming, sporulation, and the development of virulence factors such as lytic enzymes, adhesion molecules, poisons, and siderophores [23, 63]. Opportunistic bacteria like Pseudomonas aeruginosa have more than 6% of their pathogenesis-related genes controlled by QS. Early infection phases are characterized by low expression of genes linked to pathogenicity. Once population densities approach a certain threshold, QS triggers the upregulation of genes associated with virulence, leading to the progression of disease [58, 108]. There are five primary categories of signal molecules by which bacterial QS functions. These include furanosyl borate (Autoinducer-2/AI-2), methyl dodecanoic acid, hydroxyl-palmitic acid methyl ester, N-acyl homoserine lactones (AHLs), and oligopeptides (5–10 amino acid cyclic thiolactone). These include the peptide-based QS systems found in gram-positive bacteria and the AHLs generated by over 70 species of gram-negative bacteria, which have both been the subjects of much research. Peptides function through membrane-bound receptor histidine kinases, while AHLs permeate through cell membranes and attach to regulatory proteins inside the cell [66].

QS in gram-positive and gram-negative bacteria

Bacteria classified as gram-positive or gram-negative have QS (Fig. 3). The synthesis, release, and detection of signaling molecules throughout a group are all covered by the same procedure in QS processes, notwithstanding the diversity of signal component types [100]. Oligopeptides in gram-positive bacteria and N-acyl homoserine lactones (AHLs) in gram-negative bacteria were the two classes of these diffusible compounds that were primarily emphasized in a prior research investigation. In furtherance of these, autoinducer-2 (AI-2) has been proposed as a universal signal among different species due to its presence in both gram-positive and gram-negative bacteria [57]. More recently, other signal classes were also discovered, most of them were not initially classified as semiochemicals, including tropodithietic acid (TDA, which somewhat was formerly classified as an antibiotic agent until being found as a QS signal [43].

Fig. 3

The process by which quorum sensing is disrupted to prevent the production of biofilms. A AI synthesis inhibition, (B) AI degradation by AHL-lactonases, (C) AI receptor interference by AI antagonists, (D) Response regulatory interference leading to disruption of signaling cascades, (E) Reduction of extracellular AIs resulting in reduced cell-to-cell signaling. *Autoinducing peptides (AIPs) are synthesized inside the bacterial cell as pro-AIP, and their processing and modification occur either within or outside the cell, depending on the organism

I-2 Class signaling compounds

AI-2 in the Marine Phycosphere: the fact that V. harveyi mutant strains lacking in AHL production were nonetheless able to activate genes in response to a stimulus led to the proposal of a novel class of autoinducers, known as AI-2 [5]. A set of interconverting molecules formed from the precursor 4,5-dihydroxy-2,3-pentanedione (DPD) are present in AI-2 molecules. Under certain circumstances, the unstable substance known as DPD is capable of spontaneously cyclizing into distinct furanone moieties [103]. Bacteria rapidly convert DPD and use different types of DPD as their AI-2 signals. The luxS gene is the primary gene responsible for AI-2. The luxS operon consists of three genes, two of which are engaged in the activated methyl cycle. This metabolic process is crucial for the recycling of S-adenosylmethionine (SAM) [114]. Both gram-positive and gram-negative bacteria can be treated with the AI-2-QS. However, because of its varied architectures, AI-2 is difficult to identify in nature's surroundings. Utilizing the high affinity found in the V. harveyi receptor, LuxP, to match the equivalent AI-2 ligand allowed for the first investigation of AI-2 structure [16]. Vibrio bacteria found in corals and sponges in the ocean often create AI-2 molecules [59]. Numerous AI-2 homologs were discovered by metagenomics from a dinoflagellate bloom, and these homologs likely regulated symbiotic connections. The results of the investigation provided evidence that AI-2 is involved in algal and bacterial communication as well [60].

The Special Role of SAM: remarkably, SAM acts as the foundation for the production of both AHLs and AI-2. Methyltransferase enzymes and nucleosidase facilitate the transfer of the methyl group from SAM to generate S-ribosylhomocysteine (SRH). Subsequently, SRH undergoes conversion to DPD, which is the linear representation of AI-2 [140]. In addition, SAM functions as a substrate in the acyl carrier protein (Acyl-ACP) mechanism that produces AHLs. It could be beneficial to incorporate intricate chemical interactions within the bacterial community. Alkaline phosphatases (APases) became more active when long-chain-length AHLs (C10-, C12-, and C14-HSL) were added, whereas AI-2 had the reverse effect [134]. A plausible hypothesis is that a subpopulation may have used AI-2 to downregulate ATPase activity in circumstances where competitor subpopulations may benefit and AHLs to upregulate ATPase activity subsequently benefit them.

Quinolones type signaling molecules

Quinolones are a family of compounds that are structurally related to heterobicyclic compounds. These compounds differ from one another due to different carbocyclic and heteroaromatic ring replacements. Multiple members of the quinolones class possess antibacterial properties, making them potentially valuable medicines for clinical use. There are several alkyl quinolones (AQs) found in marine ecosystems, and some of these substances are used as QS signals by bacteria. An essential component of those alkyl quinolones is 2-heptyl-4-quinolones (HHQ), which are primarily synthesized by marine bacterial strains of Pseudomonas and Alteromonas [55]. HHQ biosynthesis is mediated by several genes, including pqsR, pqsH, pqsL, and pqsABCDE. Among all of them, pqsR has a crucial function in encoding PsqR, which serves as the transcriptional regulator of pqsABCDE. In addition, pqsABCDE regulates the generation of all AQs, which entails the formation of enzymes and dormant intermediates [27]. HHQ was able to impede the development of algal cells at nanomolar doses without triggering cell death [138].

Type signaling molecules of AHLs

The predominant signals in the maritime environment are AHLs. The first known QS transmitter that could regulate the luminescence produced by the marine bacteria Vibrio fischeri was N-2-oxohexanoyl-L-homoserine lactone (3OC6-HSL) [37]. The transcription-activator gene luxR, the bidirectional lux promoter, and the synthase gene luxI, which generates the signal molecule, are the genetic elements of its system that have since been studied [107]. These compounds have the same structures: an acyl chain with four to eighteen carbons and a core N-acylated homoserine-lactone ring. Gram-negative bacteria frequently have AHL-QS. Proteases homologous to V. Fischeri's LuxR transcriptional protein regulator and LuxI-AHL synthase are among its constituents. AHLs are generated by the LuxI protein and can exit the cell freely. As cell population density rises, AHL concentrations build up in the surrounding microenvironment. AHL is bonded by the receptor protein LuxR. The luxR-AHL complex subsequently induces gene expression (Fig. 4) [41]. A lengthy acyl chain is often present in AHL molecules found in the phycosphere. AHLs' acyl chains varied from C8 to C18, based on a study of over 100 distinct marine bacterial strains. AHL might be synthesized by many types of bacteria that were linked to diatoms [136]. One typical process used in the synthesis of AHLs is the extraction of the lactone moiety from S-adenosylmethionine (SAM) and LuxI enzymes [100]. There are some exclusions as well. As Emiliania huxleyi microalgae grow older, they release pCA. The roseobacters that are linked to them alter their metabolic processes to generate algaecides when exposed to pCA, and utilize pCA as a substrate for the production of p-coumaroyl-HSL (pCA-HSL) signals [113]. It has been observed that the distinct luxR-type gene varR, found in Nautella italica R11, another member of the Roseobacter group, regulates bacterial colonization and virulence. It was the primary instance of demonstrating that the luxR type gene contributes to the macroalgal illness caused by bacteria [42].

Fig. 4

Gram-negative bacteria's QS mechanism: (a) When the density of bacteria is low, LuxI catalyzes the manufacture of AHLs, which subsequently diffuse throughout the extracellular environment; (b) When the population of bacteria is high, AHLs diffuse into cells of bacteria and attach to the receptor LuxR, activating the transcription of genes under QS control

Other types of signaling molecules

Roseobacter marineus produces TDA, an antibiotic with a distinct molecular structure. The way that TDA affects the sequences of gene expression in bacteria that produce TDA suggests that TDA can function as a QS signal [56]. TDA is the QS signal used by the Roseobacter member Silicibacter sp. TM1040 in their symbiotic relationship with dinoflagellates. TDA's production necessitates the expression of tdaABCDEF (tdaA-F) and six other genes (cysI, malIJK, and tdaH), according to genetic data that implies TDA functions similarly to AHLs [44]. Indole-3-acetic acid (IAA) is widely recognized as a phytohormone that stimulates plant development through many cellular mechanisms. The latest paper highlighted its potential involvement in modulating the QS pathway. A species of Sulfitobacter that is linked with diatoms synthesizes IAA using tryptophan released by diatoms. This synthesis of IAA promotes cell division in diatoms. Before being designated as QS signals, TDA and IAA were widely recognized for their other purposes. Antibiotics, or AQs as they were previously called, fall under this category as well. The possible variety of compounds in the QS route within the phycosphere has to be further investigated [1].

QSI: the mechanism involved

QSI: hindering the signal molecule's ability

Numerous studies have been conducted to investigate the inhibition of bacterial QS and the regulation of microbial pathogenicity. Due to the absence of bactericidal or bacteriostatic properties in this method, it does not exert selective pressures and hence reduces the likelihood of resistance development. The identification of chemicals that inhibit QS is highly significant, as they can be utilized to reduce virulence, pathogenicity, and biofilm formation. This approach is especially crucial now because harmful bacteria are quickly developing antibiotic resistance. QSIs can originate from either biological or chemical sources. The former is preferred over the latter due to its non-toxic properties. Biologically active substances can be derived from a diverse range of organisms found in many ecosystems, including marine environments [29]. QSIs are produced, among others, by sponges, tunicates, fungi, algae, and marine bacteria [28]. Table 1 represents the bioactive substances of fungus and algae that are effective in downregulating QS and their possible mechanism.

Table 1 Bioactive compound of marine-derived fungal and algal source and their QSI action

Strategies for QSI or QQ, are undeniably valuable in a variety of ways, especially considering the current situation of increasing antibiotic resistance. These compounds have the potential to mitigate or perhaps completely prevent the effects of bacterial infections in people, animals, or plants [132]. The signaling molecules have a dual function in infection control and other aspects of microbiology, including host–pathogen contact, microbe-microbe communication, and microbial physiology. Microorganisms may develop signal interference strategies to adapt to different environments and compete for nutrients and ecological niches [147]. Since this method may operate on several molecular targets and impose relatively limited selection pressure on bacterial survival, its flexibility and lack of lethality are the most pertinent features from a therapeutic standpoint [132]. The use of modest dosages of antibiotics may be encouraged by QSIs as they often increase their efficiency, according to another suggested benefit [9]. The type of compound (chemical substances, enzymes), mechanism of action, and targets involved may influence how QS activities are interfered with [51]. Three primary processes, which comprise the signal synthase, the signal, and the signal receptor/transducer, can be targeted to disrupt the QS phenomena depending on the QS circuit where quenching occurs [51]. These can be broadly classified into two groups: QQ enzymes (enzymatic methods) and QSIs (non-enzymatic procedures). QQ enzymes hinder signal transmission by degrading signals, while QSIs usually consist of substances that can deactivate AI synthases or receptors through competitive binding or structural modification [76, 133]. The initial significant approach that has been explored to disrupt QS is the interference with AI detection, followed by the degradation or inactivation of signal molecules as the subsequent method [22].

Halogenated furanones, such as (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone, are the initial class of QSIs discovered and were derived from red marine algae identified as Delisea pulchra [80]. This algae is one of the extensively studied species for the production of QSIs [51]. It has been discovered that both prokaryotic and eukaryotic species produce QQ enzymes that break down QS signals [30]. Mammals such as humans have been shown to have eukaryotic QQ enzymes [19, 32] invertebrates [104, 120], other vertebrates [137]. Bacteria are widely dispersed in their capacity to squelch the QS signal via enzymes. It has been documented that some gram-positive species and the α-, β-, and γ-proteobacteria express QQ enzymes. Agrobacterium tumefaciens, Bacillus sp., Bacillus thuringiensis, Pseudomonas syringae, Bacillus mycoides, Bacillus anthracis, Bacillus licheniformis, Mycobacterium tuberculosis, Bacillus amyloliquefaciens, Acinetobacter baumannii, Bacillus megaterium, Arthrobacter sp., Klebsiella pneumoniae, Rhodococcus erythropolis, P. aeruginosa, Bacillus cereus, Rastonia sp., Variovorax paradoxus, Muricauda olearia, etc. [10]. Based on their catalytic mechanism, AHL lactonase/paraoxonase (lactone hydrolysis), AHL acylase (amidohydrolysis), and AHL oxidase/reductase (oxidoreduction) are the three forms of AHL-degradation that engage the majority of QQ enzymes [16, 133]. The majority of QSI techniques that have been reported have mostly focused on AI-1, followed by AI-2. The first one targets infections caused by a single species exclusively, whereas the second one allows for the simultaneous suppression and modification of QS mechanisms in several species [111]. While the second one allows for the simultaneous blockage and modification of QS pathways, the first one is limited to treating infections caused by a single species. QSIs can be synthesized or naturally occur in freshwater, marine, or terrestrial habitats, according to screenings. The synthesized molecules (mainly signal mimics and furanone analogs can be modified from existing chemical libraries or based on a drug design strategy. A wide array of organisms, such as fungi, bacteria, plants, and animals, naturally generate QSIs [51, 67]. The majority of the already recognized QSIs have been predominantly discovered in bacteria and plants. This may be attributed to enhanced screening methods for identifying these characteristics in both plant extracts and microbes [29, 51].

Restricting the signaling loop

Through deactivating subsequent response moderators or other regulatory elements, another way of QS system inactivation involves obstructing the signaling cascade. S. aureus AIP system, for instance, upstream signaling causes the downstream response regulator AgrA to become phosphorylated and active. AgrA then binds to DNA sequences linked to promoters and increases the expression of pertinent genes as previously mentioned. One way to stop the cascade of signals and inhibit bacteria from growing a biofilm is to suppress the response regulators. For instance, savarin is a small compound known to be an inhibitor of S. aureus pathogenicity that can specifically target AgrA to interfere with agr operon-mediated QS and hence prevent the production of biofilms [122]. Furthermore, the QS inhibitory drugs can target not only the response regulator but also other regulatory components, thereby obstructing signaling cascades. The expression of AnoR, an inhibitor of the LuxI-like synthase AnoI in Acinetobacter nosocomialis, can be repressed, for instance, by virstatin, a small substance that works to prevent the expression of cholerae virulence factors. This results in lowered synthesis of N-(3-hydroxy-dodecanoyl)-Lhomoserine lactone (OH-dDHL), which affects the signaling cascade and decreases biofilm generation and motility [94]. In addition, the use of the efflux pumps preventing PAbN decreases the amount of QS signaling molecules outside the cells and substantially decreases the expression of the QS cascade (pqsA, pqsR, lasI, lasR, rhlI, and rhlR) in P. aeruginosa clinical specimens. This reduction in QS cascade communication is subsequently followed by a decline in bacterial virulence [36].

QS Inhibitory protein and bioactive compound derived from marine fungus/algae and related by-products that exhibit QS inhibition

According to Husain & Ahmad, [61], marine plants are significant prospective candidates to interfere with QS. Delisea pulchra, a red macroalga that is sometimes referred to as seaweed, produced the first QS inhibitor and had strong antifouling action [47]. A wide array of secondary metabolites, including halogenated furanones, which are present on the algal surface, appear to be the source of the antifouling action [34]. Apart from the furan ring rather than the homoserine lactone ring, the structures of these halogenated furanones are identical to those of AHL. In the aquatic environment, dangerous and helpful bacteria coexist alongside eukaryotes including fungi, algae, and protozoa. Therefore, it is not unexpected that eukaryotes have evolved several defense strategies to deal with bacteria, such as the production of secondary metabolites that affect QS [33] or the production of secondary metabolites [108].

Considering their capacity to create a wide range of secondary metabolites, including peptides, terpenes, alkaloids derived from polyketides, and mixed biosynthetic metabolites, marine fungi were identified as potential sources of QSIs [54]. Kojic acid generated from the marine-derived fungus Altenaria sp., which was isolated from the marine green alga Ulva pertusa at Pyoseon Beach, Jeju Island, suppressed the reporter E. coli pSB401's QS-dependent luminescence when it was stimulated by N-hexanoyl-L-homoserine lactone (C6-HSL) at concentrations more than 36 μM. However, the compound only hampered LuxR reporters [79]. P. aeruginosa's swarming motility and biofilm production were both reduced by equisetin, a marine fungus Fusarium sp. Z10. Further investigation revealed that the compound reduced pyocyanin biosynthesis of P. aeruginosa PAO1 and transcriptional activation of PqsA in E. coli pEAL08-2, inhibited elastase of P. aeruginosa PAO1 and transcriptional activation of lasB in E. coli MG4/pKDT17, and decreased rhamnolipid biosynthesis, swarming motility, and transcriptional activation of rhlA in E. coli pDSY. Equisetin may inhibit the Pseudomonas quinolone signal system, las, and rhl, according to these results [148]. Asteltoxin, a QS inhibitor derived from the marine fungus organism Penicillium sp. QF046, exhibited a more potent inhibitory effect on violacein production compared to positive control, (Z-)-4-bromo-5-(bromomethylene)-2(5H)-furanone, as well as certain QS-related genes (lasA, lasB, vioB, vioI, cynS, and hcnB) that were expressed less [124].

Meleagrin, a novel bacterial enoyl-acyl carrier protein reductase inhibitor, suppressed the QS of C. violaceum CV017 with a minimum inhibitory concentration (MIC) of 138.42 mM. Meleagrin was obtained from the coastal slime of Daechun beach, Chungcheongnam-do, Korea, and is related to the marine fungus Penicillum chrysogenium [29, 150]. The biosensor C. violaceum CV026 test resulted in the separation of six QSIs from the fermentation broth of Penicillium sp. SCS-KFD08 was obtained from the marine mammal Sipunculus nudus collected from Haikou Bay, China. At a concentration of 50 μg/well, these secondary metabolites exhibited significant anti-QS activity against C. violaceum CV026. At doses below the minimum inhibitory concentration (sub-MIC) of 300 μM, compounds 91 and 92 reduced violacein production by 46% and 49%, respectively, in C. violaceum CV026 cells that were activated by the signal molecule C6-HSL [75]. Marine fungal isolates from saline waters, the rhizosphere of mangroves, and reef species were used in the screening of QS-disrupting compounds. They assessed their QS inhibitory activity with C. violaceum CV026. At doses between 50 and 500 μg/mL, four strains of endophytic fungus from the following species namely Sarocladium (LAEE06), Fusarium (LAEE13), Epicoccum (LAEE14), and Khuskia (LAEE21) showed strong activity. Following LC–HRMS investigation of these fungal bioactive metabolites, many significant compounds with previously unknown or known QSi characteristics were discovered [83]. Fusaric acid and linoleic acid, isolated from Fusarium (LAEE13) and Khuskia (LAEE21) isolates, respectively, have been demonstrated to have the ability to disrupt the QS system [119, 135, 139]. Two essential components, variecolorin N and phenylahistin, that were isolated from Epicoccum (LAEE14), were provisionally categorized as two DKPs. DKPs, when identified broadly as QSIs, can act as either QS agonists or antagonists [102]. Employing microwave-assisted synthesis, a total of 39 analogs of fusaric acid were synthesized and evaluated for their inhibitory action in three screening models for QS namely luxI-gft, lasB-gft, and rhlA-gft [130].

QSI was seen in the luxI-gft QS system at doses ranging from 6.25 to 100 μg/mL for compounds 109–114. Compound 115 showed a slight suppression of QS at 3.13 μg/mL, while a significant enhancement of QSI was seen at higher doses (6.25–100 μg/mL). At 125 μg/mL, compound 116 demonstrated excellent QSI in the lasB-gft QS system. Figure 5 illustrates the relationship between the structure of a compound and its ability to suppress QS. The presence of the C-2 ester group is necessary for inhibiting QS because it can imitate the intermolecular interaction that the lactone part of QS signal molecules requires. However, the carboxylic acid substituent at C-2 does not have any QS inhibitory activity and instead hinders the growth of bacteria. Additionally, the alkyl substituent at C-5 is not essential; even if the compounds exhibit some QS inhibitory activity, they can be substituted with an aromatic/heterocyclic aromatic ring or an alkoxy group.

Fig. 5

Structure–activity relationships obtained for fusaric acid analogs

Bacillus cereus is a prevalent food-borne pathogen that uses QS to create biofilms and produce virulence factors. The endophytic fungus Pithomyces sacchari of the Laurencia sp. in the South China Sea yielded six substances that were recognized in this study namely zinnimidine, cyclo-(L-Val-L-Pro), cyclo-(L-Ile-L-Pro), and cyclo-(L-Leu-L-Pro). The sterol derivative demethylincisterol A3 showed the strongest QSi effect against B. cereus among them. Experiments were performed to evaluate the ability of demethylincisterol A₃ to inhibit QS. Demethylincisterol A₃ exhibited a minimum inhibitory concentration (MIC) of 6.25 μg/mL against B. cereus [141].

Furanones are believed to have antagonistic effects because they may destabilize LuxR-type V. fischeri proteins, which lowers the quantity of the protein that can function as an AHL-mediated regulator [82]. The QS master regulator LuxR, which is not homologous to V. fischeri LuxR, was found to be directly targeted by natural furanone in V. harveyi. This prevented LuxR from binding to target gene promoter sequences, most likely by causing specific molecule modifications [21]. Additionally, research by Zang et al., [146] showed that the compounds also interfere with the manufacture of AI-2 by inactivating and covalently altering the LuxS enzyme. The apparent specificity of activity towards phenotypes controlled by QS may be attributed to the sensitivity of phenotypes regulated by QS to even slight alterations in the expression of QS regulatory genes. Remarkably, Bonnemaisonia hamifera, another seaweed in the same family, also showed antifouling properties [92].

Ahnfeltiopsis flabelliformis using fractionation guided by bioactivity. It was determined which metabolites were present in the polar active fractions. Although it was hypothesized that the algal metabolites causing the inhibitory activity were polyhalogenated 2-heptanones, the exact chemical composition of these molecules remains unknown. Furthermore, three novel AHL antagonists were found in the red alga by Kim et al., [73] as Isethionic acid, betonicine, and Dgalactopyranosyl-(1–2)-glycerol (floridoside). Testing of commercial isethionic acid was essential due to the unavailability of any other pure chemical alternatives. Nevertheless, the chemical did not demonstrate any QSI activity. It was postulated that the substance interacted with other compounds in a synergistic manner to impede QS. The families Rhodomelaceae, Galaxauraceae, and Caulerpaceae were shown to have minor antagonist action in their algae [117]. Teplitski et al., [127] reported that some substances released by Chlamydomonas reinhardtii replicated bacterial signals and disrupted the bacteria's QS system.

Deactivation of AHL signal-3OC₆HSL via oxidation process, another enzyme generated by algae (Laminaria digitata), bromoperoxidase, can also be used as QSI [8]. Serratia rubidaea JCM14263 was used as a biosensor in a study by [69] which revealed that 12% of the epibiotic bacteria linked to brown algae, Colpomenia sinuosa, generated chemicals similar to QSi. This indicator organism possesses an intriguing characteristic it can tolerate elevated levels of NaCl, which is necessary when the source substance is derived from marine species. The marine macroalgae Asparagopsis taxiformis showed anti-QS activity in the reporter strain of Chromobacterium violaceum CV026. The gfp-containing sensor strain Serratia liquefaciens MG44 was used to confirm the activity. 2-dodecanoyloxyethanesulfonate (C₁₄H₂₇O₅S) is the predicted active molecule that may be responsible for the QS inhibitory action, according to the ICRFT/MS results [64].

A marine fungus, namely Penicillium sp. JH1, was discovered in the offshore seas of Qingdao, China. This fungus exhibits QS activity. Furthermore, a new QSi called citrinin was extracted from the secondary metabolites of this fungus. Citrinin had a notable inhibitory effect on the synthesis of violacein in Chromobacterium violaceum CV12472, as well as on the production of three virulence factors (elastase, rhamnolipid, and pyocyanin) in Pseudomonas aeruginosa PAO1. Additionally, it has the potential to impede the development of biofilms and the movement of PAO1. Furthermore, citrinin decreased the expression levels of nine genes (lasI, rhlI, pqsA, lasR, rhlR, pqsR, lasB, rhlA, and phzH) that are linked to quorum sensing [65].

The research identified six chemicals (dankasterone A, demethylincisterol A₃, zinnimidine, cyclo-(L-Val-L-Pro), cyclo-(L-Ile-L-Pro), and cyclo-(L-Leu-L-Pro)) that were extracted from the endophytic fungus Pithomyces sacchari found in the Laurencia sp. in the South China Sea. Demethylincisterol A₃, a derivative of sterol, demonstrated potent inhibitory effect against B. cereus in the context of quorum sensing. The MIC of demethylincisterol A₃ against B. cereus was determined to be 6.25 μg/mL. Exposure to demethylincisterol A₃ led to the suppression of genes (comER, tasA, rpoN, sinR, codY, nheA, hblD, and cytK) linked to the development of biofilms, movement, and factors that contribute to virulence [141].

Marine fungal sources in down-regulating QS in ESKAPE pathogens

The group of highly virulent bacteria that pose a significant risk to humanity is referred to as ESKAPE, which comprises Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp. [45]. Marine fungal-derived QSI provide an environmentally friendly and smart approach to effectively combat microbial diseases while avoiding the typical side effects of antibiotics.

The natural chemical substance 5-episinuleptolide, which was extracted from Sinularia leptoclados, effectively reduced the development of biofilms in A. baumannii. It also showed efficacy against multidrug-resistant strains of A. baumannii by reducing the expression of poly-PNAG [129]. Various natural substances, such as patulin, clavacin, vanillin, and alliin, have been studied as QSi that disrupt AHL receptors in A. baumannii, as reported by Cady et al., [13]. Marine isolate KS8, a Pseudoalteromonas sp., showed significant QSI activity. KS8 supernatant has been shown to reduce biofilm biomass (63% during development and 33% in mature P. aeruginosa PAO1 biofilms. KS8 supernatant reduced PAO1 biofilm viable counts by 0.97-log (− 89%) and 2-log (− 99%) in biofilm formation and eradication assays, respectively. The crude organic extract of KS8 inhibited PAO1 at 2 mg/mL minimum inhibitory concentration. P. aeruginosa PAO1's QS-dependent synthesis of pyoverdin and pyocyanin was considerably inhibited by sub-MIC values (1 mg/mL) of KS8 crude organic extract without impacting growth [11]. Marine sediment-derived Penicillium chrysogenum DXY-1 ethyl acetate extracts showed anti-QS action. Purification and structural characterization revealed tyrosol, a new active substance. QS-regulated pyocyanin synthesis, elastase activity, and proteolytic activity in Pseudomonas aeruginosa PA01 reduced by 63.3%, 57.8%, and 9.9% at 0.5 mg/mL [14]. Marine fungus (Pestalotiopsis sydowiana PPR) extract proved antipathogenic. Pseudomonas aeruginosa PAO1 was inhibited by the fungal extract at a MIC of 1,000 μg/ml. QS-regulated virulence traits in P. aeruginosa PAO1 were decreased by 84.15%, 73.15%, 67.37%, 62.37%, and 33.65% at sub-MIC doses (250 and 500 μg/ml) of fungal extract. It also decreased exopolysaccharides (74.99%), rhamnolipids (68.01%), alginate (54.98%), and bacterium biofilm formation by 90.54%. P. sydowiana PPR metabolite interacts with bacterial QS receptor proteins (LasR and RhlR) resembling their native signaling molecules, according to an in silico study. In silico methods revealed P. sydowiana PPR metabolites Cyclo(-Leu-Pro) (CLP) and 4-Hydroxyphenylacetamide (4-HPA) as powerful bioactive chemicals [101].

The chloroform-based extract derived from endophytic Aspergillus fumigatus ontained from Moringa oleifera was tested against S. aureus MTCC 740 and K. pneumoniae MTCC 109 [72]. This study explored the biofilm at two stages: early cell fixation and preformed. Initial fixation experiments showed that the fungal extract inhibited S. aureus, and K. pneumoniae biofilm development by 69.2% and 57.66%. In the experiments conducted on premade biofilms, the extract demonstrated a reduction of around 51% and 53.4% in the S. aureus and K. pneumoniae biofilms, respectively. May Zin et al., [84] extracted many bioactive metabolites from the endophytic fungus Eurotium chevalieri KUFA 0006, which was isolated from Rhizophora mucronata. These metabolites were then evaluated to determine their antibiofilm efficacy against S. aureus ATCC 25923. Emodin exhibited potent antibiofilm action against S. aureus ATCC 25923, resulting in a significant 80% decrease in the staphylococcal biofilm formation. Narmani et al., [88] isolated Chaetosphaeronema achilleae from Taxus baccata and found seven chemicals in the endophyte. Overall, compounds were evaluated against S. aureus DSM 1104 biofilms. Vulculic acid exhibited significant biofilm inhibition, with 96.82% at 256 μg/mL and 91.95% at 128 μg/mL. Additionally, curvulol inhibited biofilm by 96.18% at 256 μg/mL. Metabolites chaetosindanone and curvulol also inhibited S. aureus DSM 1104.

Elkhouly et al., [35] examined the metabolic process of Hyoscyamus muticus endophytic fungus Aspergillus Tubenginses ASH4 for insight into antibiofilm chemical synthesis. Pathogenic biofilms of S. aureus ATCC6538-P and P. aeruginosa ATCC27853 were studied. The endophytic extract inhibited S. aureus and P. aeruginosa biofilms by 60.8% and 28.44%, respectively. Additionally, anophinic acid, a pure substance, inhibited the identical strains by 61.39% and 69.51%. Zhou et al., [151] performed research where they discovered that 1-(4-amino-2-hydroxyphenyl) ethanone (AHE), which was extracted from the endophytic fungus Phomopsis liquidambari S47 found in the leaves of Punica granatum, could inhibit QS in Pseudomonas aeruginosa PAO1. The chemical exerted its effects by repressing the expression of genes associated with QS, impeding the function of antioxidant enzymes, and intensifying oxidative stress. In another study, Citrinin was extracted from the fungus Penicillium sp. FF001, which was found in conjunction with the sponge Melophus sp. Citrinin had strong antibacterial properties against, rifampicin-resistant S. aureus, and Vancomycin-resistant Enterococcus faecium. Enterococcus faecium showed minimum inhibition control at a concentration of 7.81 µg/mL [121].

Another research examines the ability of red seaweed to inhibit QS in certain test pathogens, including Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter sp. The biofilm in Acinetobacter sp. was successfully decreased by 36% when exposed to a concentration of 100 mg/mL of red seaweed extract. The quantity of exo polymeric substance (EPS) from test pathogens has decreased to 40.8% in Acinetobacter sp., compared to S. aureus and K. pneumonia. The algae extract has successfully prevented the expression of the efflux pump, which is a significant factor contributing to antibiotic resistance. The algal extract A. fragilissima contains many bioactive chemicals, including Melamine, Silicic acid, diethyl bis (trimethylsilyl) ester, Trimethyl [4-(1-methyl-1-methoxyethyl) phenoxy] silane, Benzo[h]quinoline, 2,4-dimethyl, Pyrazol-3(2H)-one, 4-nitro, and 1,2-Bis(trimethylsilyl)benzene [105]. Another research was performed to examine the antibacterial and QSI properties of H. durvillei's epiphytic bacteria by isolating and identifying them. In the Philippines, researchers obtained thalli of Halodurvillei from Santa Fe, Bantayan, Cebu. Different bacterial strains tested all showed antimicrobial activity. One of the most potent inhibitory effects against Staphylococcus aureus, with minimum inhibitory concentrations, or MICs, ranging from 0.0625 to 1.0 mg ml⁻¹ [97]. Isolated and refined from the natural extract of the ocean fungus Penicillium chrysogenum DXY-1 is an anti-QS substance that inhibits the growth of Pseudomonas aeruginosa PA01. The precise molecular structure of this anti-QS material is cyclo(L-Tyr-L-Pro). At sub-minimum inhibitory concentrations, this cyclic dipeptide reduces P. aeruginosa PA01's QS-mediated pyocyanin production, proteases, and elastase activity by 41%, 20%, and 32%, individually. Furthermore, it can reduce QS gene expression in P. aeruginosa PA01 and disrupt biofilm formation [145].

Quorum Quenching in clinical and biotechnological implication

The improper utilization and excessive use of antibiotics in medical treatment, the increase in resistance to antimicrobial agents, the inability of antibiotics to effectively manage microbiological infections, and their detrimental impact on environmental sustainability. The advancement of alternate approaches to address such infections [12, 128]. QQ is an alternate method that involves inhibiting or interrupting bacterial communication or social behavior mechanically. Furthermore, QS controls the ability of microorganisms to cause disease and form drug-resistant biofilms. Therefore, targeting QS could be a viable alternative to traditional antibiotics in eliminating highly biofilm-forming pathogenic microorganisms, without contributing to the development of classical antibiotic resistance [39]. The QS inhibiting strategy is based on reducing the harmful effects of infectious bacteria without directly impacting their growth. This approach minimizes the likelihood of selection pressure and the development of resistance, ultimately enhancing the vulnerability of pathogens to the immune system of the host [116]. Therefore, inhibiting QS is a suitable approach as a therapeutic weapon against pathogenic bacteria that form biofilms and are resistant to conventional antibiotics and antimicrobial treatments. P. aeruginosa is considered a model organism for the development of anti-virulence medicines that target QS [85]. Moreover, the disruption of QS has advantages in various fields such as medicine, healthcare, water treatment, crop production, and bioreactors. This can be accomplished by interfering with QS signaling pathways or signaling molecules using quorum sensing inhibitors (QSI) or quorum quenching enzymes (QQE) [109, 112]. Over the past twenty years, there has been a significant advancement in the strategic disruption of quorum sensing (QS) to prevent or hinder the development of dangerous diseases. The QS inhibition strategies can be classified into several categories based on their functional targets. These include: a) inhibiting the production of AI molecules, b) breaking down and rendering AI signaling molecules inactive using AHL-lactonases, antibodies, oxidoreductases, etc., c) disrupting AI signal receptors by using AI antagonists to either deactivate or competitively inhibit them, d) preventing the efflux of AI molecules, and e) blocking downstream signaling cascades by deactivating downstream response regulators [152]. Furthermore, because biofilms are a crucial element in the virulence of pathogenic bacteria, infections caused by the development of biofilms on medical devices continue to be a serious issue in clinical settings [96]. A multifunctional coating based on poly (ethylene glycol) (PEG) that enables the covalent integration of the synthetic QSi 5-methylene-1-(prop-2-enoyl)-4-(2-fluorophenyl)-dihydropyrrol-2-one (DHP) into a surface can effectively decrease the formation of biofilms. Implementing this coating can also minimize bacterial colonization [152]. This offers a practical method to avoid illnesses caused by devices. Furthermore, drugs that block QS may potentially serve as antibiotic enhancers for the treatment of bacterial infections. As AHL inhibitors, two cinnamic acid derivatives, 4-dimethylaminocinnamic acid (DCA) and 4-methoxycinnamic acid (MCA), were discovered to significantly reduce biofilm formation and increase biofilm sensitivity to tobramycin [17].

Biofouling is the process of organisms adhering to a water-contacting surface. This phenomenon presents significant technological and economic challenges in various areas such as naval transportation, the aquaculture sector, petroleum sectors, healthcare equipment, bioreactors, and distribution systems for water and wastewater plants [48]. Bacteria are prevalent biofouling organisms due to their capacity to form biofilms consisting of one or more species. Initially, antifouling methods involved either physically cleaning the surface or using antibacterial substances like copper salts or metals, a technique that was already familiar to the Phoenicians between 1500 and 300 BC. Other methods included the use of detergents like benzalkonium chloride and sodium dodecylsulfate, aldehydes such as formaldehyde and gluteraldehyde, oxidizing agents like hydrogen peroxide, ozone, and chlorinated compounds like bleach or chlorine, as well as various biocides like tributyltin. These chemicals, when employed in significant quantities or enclosed spaces, provide significant health and environmental risks owing to their toxicity and ecotoxicity. Tributyltin was extensively used in antifouling paints for ship hulls throughout the 1980s and 1990s. It is the primary contaminant likely accountable for the decrease in oyster output in marine farms in France during these periods. Additional studies on the impact of tributyltin on the sexual dedifferentiation of gasteropods (known as 'imposex') have resulted in several governments globally banning the use of this compound in ship paints [31, 62]. Due to the influence of QS on bacterial biofilm development, many techniques for QQ have been proposed. The laboratory has found valuable QSI compounds with anti-biofilm action, such as the halogenated furanones derived from the red alga D. pulchra [99]. Exposure to biofouling allows other marine creatures to serve as a source of antifouling chemicals. Flustra foliacea, a marine colonial organism belonging to the phylum Bryozoa, synthesizes a collection of 10 brominated alkaloids, two of which have QSI action [51]. Skindersoe et al., [117] found that among 284 samples of marine species that were examined, 23% showed activity in a screening method based on LuxR. Out of them, a total of 36 compounds were shown to be active in a P. aeruginosa screen. Dobretsov et al., [28] conducted a study where they examined 78 products obtained from marine and terrestrial animals. They discovered that kojic acid, which is an oxo-pyrone, effectively inhibited biofouling in glass plate experiments. Recently, researchers discovered that derivatives of the diterpenes knightine, which are found in Eunicea knighti, a species belonging to the Eumetazoa phylum, can suppress bacterial biofilm formation. These derivatives were shown to be more effective at lower concentrations compared to kojic acid [126]. Despite the availability of ample data and the presence of relevant patents, the use of anti-QS tactics in the maritime sector, such as the development of antifouling paints, has not been extensively implemented. Biofouling is a significant challenge in the area of membrane filtration. Biofilm deposition on membranes in the food industry and freshwater or wastewater treatment facilities may disrupt their functionality. Multiple publications have shown the presence of a significant quantity of AHL molecules in biofilm cakes on membrane devices and have connected their existence to the production of biofilms [15]. These results led to the use of microorganisms that break down QS signals or QSI molecules to inhibit the production of biofilms. However, a strain of Rhodococcus bacteria or a genetically modified strain of E. coli that effectively broke down AHL showed positive outcomes in wastewater treatment processes [51]. Additionally, it was discovered that vanillin combined with a cellulose acetate membrane prevented the formation of biofilm in reverse osmosis systems [70, 106].

In pathogens including S. aureus, P. aeruginosa, S. marcescens, and P. mirabilis, several chemicals found in the marine environment are effective at preventing the production of virulence components that are regulated by QS. Cyclodepsipeptides, such as solonamide A, B, ngercheumicin F, G, H, and I, which are produced from P. halotolerans, have been observed to disrupt the agr QS system in S. aureus USA300 [74]. Solonamide B disrupted the interaction between AIPs produced from S. aureus and the regulatory components (histidine kinase and AgrC) of the agr system. In this particular strain of pathogens, solonamide B exhibited a reduction in the activity of key virulence factors, including α-hemolysin, as well as the transcription of the psma gene, which encodes phenol soluble modulins (PSMs). It is important to highlight that the substantial virulence associated with this strain is connected to an elevated level of α-hemolysin and PSMs expression. Thus, the strain showed reduced toxicity to rabbit erythrocytes and human neutrophils when QSIs were present [91]. Plakofuranolactone, a QSI derived from the sponge P. lita, was observed to reduce overall activity of protease, a significant virulence component linked to P. aeruginosa [20]. Methanol-based extracts of several sponges (A. bocagei, H. megastoma, and C. atrasanguinea) effectively modified the expression of virulence genes in a clinical strain of S. marcescens (PS1). The extracts demonstrated the ability to hinder the generation of pigment (prodigiosin) that depends on AHL, and to regulate the creation of biofilm and the activity of enzymes linked with virulence (protease, hemolysin) [2]. Protease, haemolysin, lipase, prodigiosin, and extracellular polysaccharide were among the QS-regulated virulence parameters that were adversely affected by PD [phenol, 2,4-bis(1,1-dimethylethyl)] that were obtained from V. alginolyticus G16 in S. marcescens, but growth was unaffected [98]. Furthermore, it has been observed that marine Streptomyces species-derived culture supernatants reduce QS-dependent virulence factors in P. mirabilis, including hemolysin, urease activity, and motility [144]. These substances can be utilized to create new medications by reducing the synthesis of pathogenicity and virulence factors.

Conclusion

The marine environment is a plentiful source of bioactive chemicals, including QSIs. QSIs molecules are synthesized by marine organisms such as algae, fungi, bacteria, and other invertebrates. The discovery that QS controls the ability of many disease-causing bacteria to cause harm, along with the observation that certain marine microorganisms and their secondary metabolic products can disrupt QSi, suggests that the bioactive compounds derived from marine organisms could be used to treat bacterial infections. In the domains of pharmaceuticals, the presence of pathogenic bacteria that possess genes linked to virulence is of utmost importance, and QS plays a vital role in regulating these activities. It is imperative to thoroughly examine the pathogenicity mechanisms of these diseases, particularly because of their connection to QS. In addition, further investigation is necessary to ascertain the exact correlation and influence of QS on the interplay among the numerous organisms present in the marine ecosystem including the mechanisms of action necessary to determine their therapeutic potential. QSI synergistic interactions with various anti-infectives should be investigated for more combinatorial disease treatments. The absence of methodological standards in QSI efficacy evaluation limits the general validity of any results. Furthermore, more research on down regulation of ESKAPE pathogens are required. Using purely laboratory-adapted strains in this area may be a significant error, as they may differ significantly from the pathogens responsible for serious clinical disorders. Hence, future research and development of QSIs must conduct additional testing under conditions that closely match in-vivo pathogenic illnesses. It is certain that using inhibitors for many targets at the same time, such as the QS system, will benefit to combat bacteria especially pathogenic that are resistant to multiple antibiotics. Industrial and biotechnogical implication of QQ has been performed previously which has positive perspective but the more exploration in the direction of theraputic angle is highly required.