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Pathogenic bacteria cause infectious diseases, mainly when the host (humans, animals, and plants) are colonised by bacteria, especially in its biofilm stage, where it is known to cause chronic infections. Biofilms are associated with resistance to antimicrobial agents, including antibiotics, antiseptics, detergents, and other therapeutic approaches. Antimicrobial resistance (AMR) is one of the biggest public health challenges of our time and is termed a ‘silent pandemic’ by the United Nations. Biofilm formation, pathogenicity and the associated AMR are regulated through a bacterial cell-to-cell communication system termed “Quorum Sensing (QS)’. As the bacterial cells sense the fluctuations in their population, they biosynthesise and secrete the signalling molecules called autoinducers (AI). In gram-negative, the signalling molecules are primarily homoserine lactones (AHL) whereas in gram-positive the signalling molecules are autoinducing peptides. The AI binds to receptor and regulator proteins in the bacterial cells to activate the complete QS system, which controls the regulations of various genes that are essential for the biosynthesis of virulence factors, extracellular biopolymers (EPS) production, biofilm formation and bacterial fitness.
Infection, Immunity and Inflammation Theme, Sydney Institute for Infectious Diseases, Charles Perkins Centre, School of Medical Science, The University of Sydney, Australia
Brandon C. Young
Infection, Immunity, and Inflammation Theme, Charles Perkins Centre, School of Medical Science, The University of Sydney, Australia
*Address all correspondence to: das.ashishkumar@sydney.edu.au
1. Introduction
Infectious diseases of humans, animals and plants are caused by the spread of microorganisms, including bacteria, fungi, viruses, protozoa and parasites. Microorganisms that cause disease are called pathogens. Our body (gastrointestinal tract, skin, mucosa of mouth, nose and vagina) is inhabited by numerous bacterial species that form part of the host commensal microflora [1]. However, under certain circumstances, when the host immune system is compromised due to diseases such as HIV, cancer, COVID-19, cystic fibrosis or when the individual has burn injuries, blunt trauma or penetrating trauma (such as through surgery), bacteria can breach the host barriers and colonise to cause infection. Such bacteria are called opportunistic pathogens. Pathogenic bacteria cause infectious diseases, often when they colonise and form biofilms. Biofilms significantly impact human health; it is estimated that 65% of all microbial infections and more than 80% of chronic infections involve biofilm-associated microorganisms [2]. In this chapter, we have discussed a few of the clinically important biofilm-associated infections.
Urinary tract infections (UTIs) are infections involving any part of the urinary tract. They are one of the most common infections, resulting in an estimated 7 million office visits, 1 million emergency department visits and over 100,000 hospitalisations annually in the United States [3]. UTIs are caused by both gram-negative and gram-positive bacteria, with the most common causative agent for both complicated and uncomplicated UTIs being uropathogenic Escherichia coli (UPEC), causing approximately 75% and 65% of these cases, respectively, with other notable contributors including Staphylococcus saprophyticus, Enterococcus faecalis, Group B Streptococcus (GBS), Proteus mirabilis and P. aeruginosa [4]. UPEC, as well as many of the other common uropathogens, establish biofilms on the bladder wall and surfaces of indwelling urinary catheters as a strategy to protect the encased bacteria from the host immune response and intervention with antimicrobial therapy [5, 6].
Microbial keratitis is an infection of the cornea; when mismanaged, this infection can result in scarring of the cornea, permanent loss of vision and even total loss of the eye [7]. In the United States alone, there are nearly 1 million clinical visits for keratitis annually at an estimated cost of US$175 million in direct health care expenditures [8]. Biofilms play an essential role in bacterial keratitis as their presence on contact lenses as well as their storage cases can allow bacteria to survive and eventually spread to corneal epithelium [9]. Biofilm populations have increased resistance to antibiotics and host immune response [10]. Bacterial keratitis is significantly more prevalent than fungal keratitis in the United States and other developed countries and is commonly caused by S. aureus and P. aeruginosa.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterised by poorly reversible airway obstruction and is currently the third leading cause of death worldwide [11]. The lower respiratory tract of COPD patients is often colonised by bacteria, such as P. aeruginosa, Haemophilus influenzae and Streptococcus pneumoniae [12, 13]. Chronic bacterial colonisation is a major factor driving chronic inflammation in COPD patients [14]. Exacerbations are one of the most important manifestations of COPD and are defined as an increase in the inflammation present above the stable state of COPD, and COPD patients are estimated to suffer 1−4 exacerbations annually [15]. Exacerbations are thought to worsen the decline in lung function with increasing exacerbation frequency, are responsible for much of the morbidity and mortality of COPD [16], account for 50%−75% of the total economic burden due to COPD [17] and estimated to be US$32 billion annually in the United States alone [18]. Respiratory infections are the most common cause of severe exacerbations in COPD, with P. aeruginosa being one of the most frequently isolated causative microorganisms in severe COPD patients [19, 20].
Seasonal respiratory viruses such as influenza virus and respiratory syncytial virus (RSV) as well as respiratory viruses that have spread in major outbreaks such as SARS-CoV, H1N1 Influenza, MERS-CoV and SARS-CoV-2 are a significant cause of morbidity and mortality worldwide. Following the primary viral infection, disruption of the airway epithelium barrier and dysregulation of immune responses promote the colonisation of various bacteria to establish secondary bacterial infections, also known as superinfections, which can have significantly worse clinical outcomes when compared to the initial primary infection [21, 22]. Among COVID-19 patients, secondary bacterial infections can arise due to subsequent colonisation by Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa and other bacteria [23], and it has been observed that patients with these superinfections are seen to have mortality rates twice as high as those without secondary bacterial infections [24].
Biofilm formation is the most complex stage in the bacterial lifestyle [25]. Compared to the planktonic stage or free-living bacterial cells, bacterial cells encased within biofilms are highly resistant to antimicrobial agents, detergents, host immune responses and environmental and physical stress [26, 27]. Researchers in many publications have widely described the mechanism of biofilm formation [28]. Figure 1, in brief, represents schematically bacterial biofilm formation in a hierarchical process.
To begin with, motile planktonic bacterial cells travel towards the substratum surface (e.g., mucosal, skin, biomaterials and other non-biotic surfaces) and reversibly adhere. In this step, the motility and adhesion are facilitated by flagella, fimbriae, pili, outer membrane proteins (OMPs) and lipopolysaccharides (LPS). These cell appendages and biomolecules drive non-specific physical-chemical forces (e.g., Lifshitz-van der Waals and electrostatic interactions) [29].
In the second step, bacterial irreversible/strong adhesion to the surface is also driven by bacterial cell appendages, OMPs and LPS. Again, the physicochemical forces drive these interactions (van der Waals, electrostatic interactions, acid-base interactions and hydrophobic forces). These interaction forces promote the transition from initial reversible bacterial adhesion to the irreversible phase, over several minutes by progressive removal of interface water between the bacterial cell surface and substratum or another bacterial cell surface. In addition, bacterial cell surface biopolymers such as proteins and eDNA undergo conformation changes that suit bacterial attachment to the surfaces [29].
In the next step, bacterial cells secrete signalling molecules with increasing bacterial population (e.g., Homoserine lactone, auto-inducing peptides and competence stimulating peptides). These signalling molecules bind with the bacterial cell membrane-bound receptors or/and transcriptional regulatory proteins to initiate the quorum sensing (QS) system in bacteria [29]. QS is essential to trigger bacterial aggregation and microcolony formation.
In the fourth stage, the QS-mediated biosynthesis and secretion of virulence factors and other extracellular compounds, including polysaccharides, eDNA, proteins and metabolites, occur and dictates robust biofilm matrix and maturation of biofilms. The robust biofilm matrix hinders antibiotic penetration into biofilms and can provide resistance against antibiotics for the encased bacteria up to 1000-fold [30]. The biofilm matrix is termed a “house of biofilms’ [31].
In the final stage, biofilm ageing and dispersion of mature biofilm as planktonic bacterial cells occur, allowing for bacterial attachment and biofilm formation at new sites through a repeat of the biofilm cycle. The dispersion stage is essential for expanding bacterial colonisation and survival and is triggered through active and passive mechanisms. In the active mechanism, bacteria produce various enzymes/proteins (e.g., DNase I, Alginate lyase, Dispersin B, Exopolysaccharide lyase, protease, surface-protein-releasing enzyme, etc.). These enzymes cleave the biofilm matrix and trigger the release of bacterial cells. The passive dispersal mechanism is mainly the external environment, including nutrient deficiency, QS signals, phagocytosis and antimicrobial agents [32].
Figure 1.
Schematic showing the five major steps involved in the biofilm formation cycle. The cycle begins with mobility and initial adhesion to the substratum and eventually results in a mature biofilm in which bacteria can disperse as planktonic cells to colonise new sites and repeat the cycle.
3. Physical: Chemical forces influence bacterial adhesion and program biofilm formation
Many studies have acknowledged that the fundamental physical-chemical interaction forces observed throughout the biofilm formation cycle are essential for mature biofilm formation. The physical-chemical interaction forces mediated by bacterial cells or substratum surfaces are purely dependent on the presence of chemical functional groups and the charge of molecules on surfaces. For instance, Das et al. 2012 showed that removing eDNA from Streptococcus mutans cell surface via DNase I treatment significantly decreases short-range acid-base interaction forces between bacteria and surface and consequently impaired S. mutans adhesion to the glass substratum surface [33, 34]. In another study, Swartjes et al. 2015 showed similar inhibition of P. aeruginosa and S. aureus adhesion and biofilm formation on DNase I immobilised surfaces [35].
Thermodynamics and extended Derjaguin−Landau−Verwey−Overbeek (DLVO)-analyses theoretically revealed that long-distance van der Waals interaction forces are always favourable or attractive due to the induced dipole interactions. These forces are weak and can range up to hundreds of nanometres and are essential to initially bringing bacteria closer to the substratum [29].
Electrostatic interactions are purely dependent upon the surface charge of bacteria and substratum. Bacterial cell surfaces are generally negatively charged due to the presence of negatively charged biopolymers and cell appendages. Electrostatic interactions would predict repulsion between bacteria and surfaces if the substratum surface also exhibits a negative charge [29, 34], whereas bacteria should rapidly attach to positively charged substratum surface. It is to be noted that many antibiotics (e.g., Gentamicin, tobramycin, etc.) or antimicrobial peptides (bacitracin, colistin/polymyxin E and B) are naturally or engineered to be cationic charged to enhance their interactions with bacterial cells [36]. Also, antimicrobial surfaces are made by immobilising cationic antimicrobial polymers to attract bacterial adhesion and kill without inducing biofilm formation [37]. Electrostatic forces are also influenced by the presence of nutrients such as divalent cations (Ca2+ and Mg2+), which promote bacterial interactions, aggregation and biofilm matrix stability by interacting between negatively charged biopolymers within the matrix [38, 39].
Short, ranged acid-base interactions come into action when bacteria are at very close range to the substratum (below 5 nanometres). These forces are influenced by the presence of polar moieties in the molecules; polar groups promote electron-accepting or electron-donating parameters that are essential for bond-strengthening and transition from reversible bacterial adhesion to irreversible adhesion stage. An atomic force microscopic study performed by Das et al. 2011 revealed that bacterial cell surfaces containing eDNA had more vital adhesion forces, multiple minor peaks (due to bond breakage) and a more significant separation distance than DNase I treated bacterial cells [34]. This means eDNA favours bond-strengthening mediated by close-range acid-base interactions (triggers by electron donation and accepting moieties in the eDNA) [29, 34].
Hydrophobic forces are also one significant factor determining bacterial adhesion to the surface and biofilm formation. Studies have shown that hydrophobicity of surfaces (bacteria or substratum) promotes bacterial adhesion and biofilm formation [34, 40, 41]. Hydrophobic forces are strong interactive solid forces compared to van der Waals and hydrogen forces. Garcia-Fernandez et al. 2021 showed that EPS-producing strains of Streptococcus thermophilus and Lactococcus lactis spp. have a higher water contact angle (hydrophobicity) than EPS-negative mutants [42]. EPS production by these strains is directly related to its robust biofilm formation ability [42]. Contact angle analysis has also revealed a significant change in bacterial cell surface hydrophobicity when subjected to DNase I treatment: P. aeruginosa PAO1 strain water contact angle is 65O when exposed to exogenous DNA whereas, when not exposed to exogenous DNA the water contact angle is 44O [34]. Hydrophobic and van der Waals interactions are essential for maintaining biofilm stability by interacting with different biopolymers within the matrix, e.g., carbohydrates and proteins [43]. A study revealed that in Burkholderia multivorans, EPS component polysaccharide (EpolC1576) holds many non-polar rhamnoses (6-deoxy sugar) units in its primary structure; these non-polar units influence rhamnose binding with many hydrophobic molecules and are essential for the architecture of three-dimensional biofilm matrix [44].
Mirani et al. 2016 have shown that bacteria can change their cell surface phenotype i.e., hydrophilic to hydrophobic and vice versa when exposed to antibiotics [45]. Their study showed that when S. aureus is exposed to a sub-inhibitory concentration of oxacillin, S. aureus changes to biofilm mode and its cell surface hydrophobicity increases in contrast to its planktonic phase characterised by more hydrophilic character [45]. Another interesting finding is that in S. aureus and P. aeruginosa biofilms, the small colony variants (SCVs), which are metabolically inactive (but viable and non-culturable bacterial cells), exhibited hydrophobic properties [46]. These SCVs play a critical role in the persistence of infection and pathogenicity [47, 48].
Through the decades of research, it has been well acknowledged that the QS system is an essential phenomenon for the bacterial biofilm lifestyle. The principal purpose of bacterial QS is to control the regulation of gene expression related to bacterial biosynthesis of numerous endo and exogenous molecules critical for necessary bacterial fitness, survival, virulence production, biofilm formation, infection of the host, evading host immune response and antimicrobial agents. QS is a step-by-step mechanism that begins with bacterial population density fluctuations triggering the release of signalling chemical molecules called “autoinducers’. Studies suggest that autoinducers influence bacterial communication (i.e., ‘calling distance’) at ranges between 5 and 200 μm [49, 50]. Autoinducers could be of different types and classes [51]. For example, most gram-negative bacteria (e.g., P. aeruginosa, E. coli, A. baumannii, Vibrio Cholera, etc.) produces homoserine lactone molecules of different molecular weight and carbon length. At the same time, gram-positive bacteria (e.g., Staphylococcus sp. and Streptococcus sp.) produce autoinducing peptides and competence stimulating peptides as their signalling molecules. Once secreted, autoinducers get recognised by bacterial cell membrane-associated or intracellular receptor proteins. In addition to population-based naturally secreting autoinducers/signalling molecules, many other environmental factors, including oxidative stress, antibiotics or antimicrobial chemicals or nutrients, trigger QS in bacteria.
The typical gram-negative and gram-positive QS mechanisms have been illustrated in Figure 2.
Figure 2.
Schematic showing the quorum sensing (QS) mechanism in gram-negative and gram-positive bacteria. In gram-negative bacteria, the signalling molecule is primarily AHLs, whereas in Gram-positive bacterial species, signalling molecule is primarily by AIPs, followed by bindings of signalling molecules to the receptors in a bacterial cell and triggering activation of QS-controlled genes. Regulation of Qs genes influences virulence factor production and biofilm formation.
4.1 P. aeruginosa is a classic example of a hierarchical QS system
In most gram-negative bacterial species, luxI-luxR genes or homologous genes regulate the QS system. In P. aeruginosa, there are four principal QS systems. First, lasI/lasR genes are homologous to the lux system and are responsible for the biosynthesis of the chief lactone-based signalling molecule/autoinducer N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12-HL). The gene lasI encodes the autoinducer enzyme LasI, which acts to catalyse the synthesis of the lactone autoinducer (also called AI-1) from substrates 3-oxo-C12-acyl-carrier protein (acyl-ACP) and S-adenosyl-L-methionine [52, 53]. The homoserine lactone molecules are generally lipophilic and freely diffuse through the lipopolysaccharides in the P. aeruginosa cell membrane out to the immediate external microenvironment. The AI-1 then binds with the intracellular transcriptional LasR protein (in this case, LasR functions as both AI binding protein and regulatory protein) to activate various virulence factors genes, including exoprotease (lasA), elastase (lasB), alkaline protease (aprA) and endotoxin A (toxA), Phospholipase C, heat-labile hemolysin (plC), and lasI (for positive autoregulation) [54, 55].
Next in the QS hierarchy is the RhIl-RhIR system. The RhlI (encoded by rhlI) autoinducer synthase enzyme synthesises N-butyryl homoserine lactone (C4-HSL) binds with transcriptional regulatory protein RhlR. RhlR- C4-HSL interactions lead to the activation of several other virulence genes, including rhlAB (rhamnolipids) and lasB (elastase B) in Pseudomonas species [53, 54, 55].
The PQS-PqsR QS system is a late QS system responsible for producing a phenazine-based cytotoxic metabolite 1-hydroxy-N-methylphenazine (pyocyanin) [54]. Operons pqsABCDEHR and phnAB and genes outside these operons are responsible for synthesising the pseudomonas quinolone signal (PQS) autoinducer in a complex multistep process [56]. The receptor for PQS is the PqsR protein (pqsR), which is regulated through the AHL-LasR QS system [54, 57, 58, 59]. The binding of the PQS autoinducer to the PqsR receptor/regulator protein activates the expression of virulence factors, including phz (pyocyanin), which are critical for causing infection. PQS signalling molecules also act as siderophores in chelating ferric ion (Fe3+) and activate the production of siderophore genes pvd (pyoverdine) and pch (pyochelin) [57, 58, 59, 60, 61, 62].
A newly identified class of autoinducer, termed IQS (2-(2-hydroxyphenyl)-thiazole-4-carbaldehyde), has been recognised in P. aeruginosa and categorised into a fourth QS system known as the AmbBCDE/IqsR system [63, 64]. This system can integrate environmental stress cues such as phosphate depletion into QS signalling to activate PQS-PqsR signalling in the absence of LasI-LasR activity [65].
QS-mediated toxin biosynthesis induces a severely detrimental effect on the host body. For instance, endotoxin A constrains protein synthesis in the host by impeding protein elongation factor 2 [66]. Exoenzyme S quests on low molecular weight proteins in the host, consequently hindering DNA synthesis and cell morphology [67]. Elastase from P. aeruginosa cleaves human leukocyte elastase, human neutrophil elastase and collagens, destroying host tissue elastic properties and impairing wound healing [68, 69]. Production of hemolytic phospholipase C (PlcHR) by P. aeruginosa directly interferes with the host protein kinase C signalling pathway (PKC), thus restraining neutrophil burst activity and superoxide (O2.−) production [70]. Neutrophil assembly and production of superoxides at the infection site are essential to fight against P. aeruginosa pathogenicity. Thus, PlcHR promotes P. aeruginosa survival in host tissue by evading host inflammatory response by restraining neutrophil burst activity [70].
Pyocyanin, a hallmark metabolite of P. aeruginosa, gives a unique greenish-blue colour when grown in the lab and is also visible at the infection site. For instance, Green Nail Syndrome (GNS) is a nail infection caused by P. aeruginosa, and the presence of pyocyanin (also siderophore pyoverdine) causes the greenish colourisation of nails (chloronychia) [71]. Pyocyanin diffuses into host cells and reduces intracellular thiol antioxidant (glutathione) levels in mammalian cells [72]. In vitro study showed pyocyanin induces oxidative stress in cells, hinders human nasal ciliary beat frequency, declines intracellular cyclic AMP and damages epithelium [73]. Pyocyanin has been found in burn wound exudates; from burn wound patients and is known to impair wound healing by triggering cell-cycle arrest and premature senescence (ageing of cells) [74, 75]. Pyocyanin is essential for biofilm matrix stability via intercalation with eDNA [76]. Pyocyanin-DNA binding is necessary to prevent the loss of pyocyanin to the external environment and supports P. aeruginosa cells in inner biofilm layers that lack oxygen [77].
4.2 Highlighting QS regulation in gram-positive bacteria
In gram-positive bacteria, the peptide-based QS system is critical in virulence factor production and biofilm formation. For instance, in Streptococcus species (Streptococcus pneumoniae and S. mutans), competence stimulating peptide (CSP) is the primary autoinducer whose synthesis is regulated by comE [78]. The CSP gets released extracellularly via the transporter protein ComAB. In the extracellular microenvironment, CSP autoinducers bind with bacterial membrane-bound receptor ComD (transmembrane histidine kinase), causing the phosphorylation (i.e., transfer of phosphate group) of the regulatory protein ComE [78]. ComE undergoes structural modulation and binds with the promoter region of DNA to promote QS regulation genes and virulence factors [79]. CSP-Com mediated QS induces bacterial cell lysis proteins, including murein hydrolases autolysin A and C (LytA and LytC) and Choline-Binding Protein D (CbpD) [80]. These proteins trigger fratricide in the pneumococcal population and trigger virulence factors pneumolysin and Streptococcus cell wall constituent lipoteichoic acid (LTA) into the host cell to trigger an immune response [80]. CSP is essential for Streptococcus-mediated DNA binding, uptake and transformation from the microenvironment [81] and eDNA-mediated biofilm formation [81]. Other receptors and transcriptional regulatory proteins have also been identified that bind signalling peptides or activate through external environmental factors (oxygen, acid, oxidative stress) and coordinate QS systems in the Streptococcus species, including BlpABCSRH, CiaRH, HK11/RR11, VicK/VicR and LytST [82, 83]. This QS system is essential for other virulence factor synthesis such as capsular polysaccharides to evade the host immune response (phagocytosis) in S. pneumoniae, antibiotic resistance, acid and oxidative stress tolerance and biofilm integrity [84, 85, 86, 87].
In S. aureus, multiple QS systems have been reported. The primary QS system is coordinated by the global regulatory QS system called accessory gene regulator (agr). Through agr QS system this bacterium deploys a wide collection of virulence factors to establish biofilms and infections [88]. One of the crucial roles of the agr QS system is to encode a signalling circuit that biosynthesis and sense the autoinducers (AI and AIP) and the intracellular effector RNAIII [89]. The autoinducing peptides and agrABCD proteins coordinate the QS system and are essential for expressing exotoxin hemolysin (hla and hlb), toxic shock syndrome toxins (tsst) and controlling biofilm formation and dispersion [90, 91, 92, 93]. Other autoinducer binding proteins in S. aureus include KdpD/E, KdpD being a receptor protein that binds with autoinducer-2, whereas KdpE is a regulatory protein triggered via phosphorylation [94]. Autoinducer-KdpD/E system regulates capsular polysaccharide biosynthesis in S. aureus. VraSR is another two-component signalling system that gets activated via environmental factors, i.e., by sensing the presence of bacterial cell wall inhibitor compounds such as antibiotics [95]. This system’s primary role is to regulate cell wall biosynthesis, impair antibiotic effects and develop resistance [95, 96].
5. Anti-QS strategy to encounter bacterial biofilms and their pathogenicity
The introduction of antibiotics (e.g., discovery of penicillin in 1928) into clinical medicine has drastically improved human health, allowing for effective treatment of life-threatening infectious diseases and the ability to perform medical procedures previously avoided due to the high risk of postoperative infections [97, 98]. However, with the immense rise of AMR, existing antibiotics show less effectiveness in treating microbial infections. Developing novel antimicrobial agents and new strategies are critical to overcome biofilms and associated AMR in the medical arena. Antibiotic resistance is rapidly spreading and a major concern, with estimates that by the mid-21st century, antimicrobial resistance could contribute to 10 million deaths each year and cost the global economy US$100 trillion [98].
Widespread antibiotic resistance is driving an intense search for novel therapeutic approaches. Interfering with QS, termed quorum quenching (QQ), has been an area of interest in this space with the aim of inhibiting bacterial virulence and biofilm formation [99]. QS inhibitors can reduce bacterial virulence and alleviate symptoms of microbial infections in a non-bactericidal or bacteriostatic manner, hence relaxing selection pressure for resistance to these molecules while also not affecting beneficial bacteria [100, 101]. Table 1 summarises a few examples of QS inhibiting molecules and their mechanism of action against different pathogenic bacteria.
Type of Quorum Sensing Inhibitors
Bacteria target
Mechanism of action
References
Halogenated furanone from marine alga Delisea pulchra. Ascorbic Acid (Vitamin C) Synthetic furanone (C30 and C56)
Highlighting the anti-QS molecules and their mechanism of action against various bacterial pathogens.
One historic discovery in QS inhibition was halogenated furanones derived from red alga Delisea pulchra [116] and early work demonstrating their impact on QS behaviours such as inducing irregular non-coordinated swarming in P. mirabilis [102]. Many furanones are now known to act as competitive inhibitors of LuxR-type receptors in gram-negative bacteria by competing with AHL for binding to reduce QS signalling [103]. Following the discovery of halogenated furanones impact on QS, much research was carried out to test synthetic furanones as a potential treatment for microbial infections and it has shown success within mouse models to reduce P. aeruginosa pathogenicity and enhance bacterial clearance within lungs [104].
Ascorbic acid (vitamin C) is a natural furanone relevant to human health. Ascorbic acid has long been known as an important molecule for normal physiological functions, playing important roles as an antioxidant to protect the body from free radicals and improving immune system function by increasing lymphocyte proliferation, natural killer activity and aiding in chemotaxis [117]. Ascorbic acid is now known to be a potent inhibitor of QS within P. aeruginosa. It has been shown to inhibit pyocyanin production and attenuate biofilm formation [105].
Flavonoids are a class of polyphenolic secondary metabolites found in plants. Quercetin is a flavonol ubiquitous in vegetables, fruits and plant-derived drinks such as tea and wine [118]. Flavonoids such as quercetin have been extensively studied for their cardioprotective, anticarcinogenic, antioxidant and anti-inflammatory effects [119, 120, 121]. Additionally, quercetin is an effective QS inhibitor in P. aeruginosa, with research showing it can inhibit biofilm formation and initial bacterial adherence and reduce virulence factor expression [106]. Evidence suggests that quercetin acts as a competitive inhibitor of the LasR receptor, competing with AHL for binding to reduce QS signalling in P. aeruginosa [107].
Curcumin is another polyphenol and is the distinctive yellow pigment and a major constituent of turmeric derived from the Curcuma longa plant. Curcumin has a rich history in traditional medicine for its use in anti-inflammatory and antimicrobial roles. Recent research has proven curcumin anti-QS in numerous pathogens. In Chromobacterium violaceum, curcumin inhibits violacein pigment production controlled by QS [108]. In Salmonella serovar Montevideo, curcumin is seen to inhibit biofilm formation, and in Serratia marcescens, it can completely inhibit swarming motility [109]. In P. aeruginosa, curcumin attenuates biofilm formation and down-regulates virulence factors such as pyocyanin and elastase [110]. Silico analysis suggests that curcumin also acts as a competitive antagonist of LuxR-type receptors [111].
Gram-positive bacteria such as S. pneumoniae participate in QS through secreting oligopeptides as autoinducers. The competence regulon is a QS circuit present within S. pneumoniae and is centred on the competence stimulating peptide (CSP), the AI oligopeptide [122]. Two main CSP variants exist, CSP1 and CSP2, which bind to their corresponding histidine kinase receptors ComD1 and ComD2 to drive virulence factor production and biofilm formation [123, 124]. Synthetic peptide analogues have been explored to inhibit QS in peptide-based QS systems. Dominant-negative competence-stimulating peptides (dnCSPs) are one such example. They can reduce virulence factor expression in vitro and attenuate pneumococcus infections in mice by competing with CSP for ComD binding [81, 112].
QS inhibition can also be achieved by enzymatic degradation of AIs. This mechanism has been a major focus within QS inhibition research for gram-negative bacteria, and many QQ enzymes from prokaryotic and eukaryotic origins have been discovered [125]. QQ enzymes targeting AHL in gram-negative principally involve four types of enzymes, AHL-lactonases and decarboxylases hydrolyse the lactone ring, whilst AHL-acylase and deaminase cleave the acyl side chain, ultimately leading to reduced AHL-Lux receptor binding and decay of the QS signalling [125]. Many research examples of QQ enzymes show success in QS inhibition within many different bacteria; in one example, an engineered lactonase originally isolated from Sulfolobus solfataricus was seen to reduce virulence in clinical isolates of P. aeruginosa with pyocyanin production, protease secretion and biofilm formation all inhibited [113].
QQ antibodies are a novel approach to QS inhibition. AHLs and autoinducing peptides have low molecular weights; consequently, they are poorly immunogenic and not expected to elicit an antibody-based immune response [125]. However, hapten–carrier strategies can overcome this lack of immunogenicity by attaching AHL molecules to carrier proteins before immunisation. Miyairi et al. synthesised a carrier protein-conjugated 3-oxo-C12-HSL (P. aeruginosa HSL) and immunised mice prior to intranasal challenge with P. aeruginosa [114]. Immunisation generated high titres of specific antibodies to 3-oxo-C12-HSL, which was strongly associated with a survival benefit in mice [114]. Bacterial numbers in the lungs did not differ between control and immunised groups, and the increased survival of immunised mice was suggested to be through blocking an excessive pro-inflammatory host response through suppression of virulence factors under QS control [114]. In a similar approach, antibodies targeting Staphylococcal autoinducing peptides (AIPs) show potent QQ abilities and increasing protection of mice challenged with S. aureus [115].
Biofilm formation by opportunistic pathogens and its associated AMR has a catastrophic effect on society. Despite extensive research on bacterial biofilms carried out over the past century and AMR in the past few decades, we are yet to fully understand bacterial biofilms and the bacterial strategy to evade host immune responses and antibiotic therapy. The discovery of the QS mechanism in bacterial lifestyle is ground-breaking research that has revealed various behaviours and processes under its control, including adaption to physical and chemical stress, expression of genes that regulate extracellular polymeric substances, metabolite production, the integrity of biofilm matrix, efflux pumps to reduce intracellular antibiotic concentration and various antibiotic cleaving enzymes such as beta-lactamase and macrolide esterases, etc. The discovery and use of natural QS inhibiting molecules such as plant-based curcumin, vitamin C, polyphenols (flavonoids) from green tea and furanone from red algae, as well as the subsequent development of synthetic molecules have provided an innovative strategy to tackle bacterial infection and AMR and may play a critical role in the future to address to the continual spread of AMR in many clinically important bacteria and their increasing burden on human health.
There is a multitude of factors that influence the rise of bacterial-associated infections, AMR and consequently mortality. In developing countries, the burden is disproportionately high due to various factors, including high population density, inadequate and unaffordable healthcare, poor education leading to inappropriate use of antibiotics (e.g., prescribing antibiotics against common cold and seasonal viral infections), political factors including poor governance that does not provide the necessary infrastructure and policies related to healthcare, sanitation, hygiene, etc. Tangible measures are essential for governments and corporate sectors to ensure the availability of basic facilities to circumvent the increase in bacterial-associated infections, AMR and its associated mortality and morbidity. Developing innovative ideas, new drugs or improving existing drugs through increased financial support to research institutes, universities and the pharmaceutical industry is critical to addressing AMR and ultimately improving global health.
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Written By
Theerthankar Das and Brandon C. Young
Submitted: 06 May 2022Reviewed: 20 July 2022Published: 26 August 2022
Open access peer-reviewed chapter
