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Pseudomonas Aeruginosa 

Even though Pseudomonas aeruginosa has been recognized as a prominent bacterial pathogen since the 19th century, it has only been within the last 50 years that this organism has emerged as one of the most frequent causes of nosocomial bacterial infections. This is mostly because of contemporary medical treatments that offer environments where P. aeruginosa can colonize and infect vulnerable patients [x].  Environmentally common and carbapenemase-resistant Pseudomonas aeruginosa is a clinically serious opportunistic human infection and one of the key diseases on the WHO priority pathogens list [x].  Pseudomonas aeruginosa is also resistant to several other antibiotics, which makes treatment extremely difficult [x]. Here we explore microbiome research for cutting-edge treatment options.

1. Virulence Factors of Pseudomonas Aeruginosa 

Pseudomonas aeruginosa is a bacterium that can quickly acquire antibiotic resistance, adapt to environmental changes, and produce various virulence factors.   These virulence factors aid in the development and survival of p. aeruginosa by manipulating the host’s cellular machinery and inflicting severe wounds, tissue necrosis, immune system evasion, and dysfunction [x].

P. aeruginosa can either cause an acute infection by rapidly expanding and dispersing throughout the host or they can adopt a persistent biofilm infection strategy [x].

1.1 Lipopolysaccharides (LPS) 
Lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria, has been found in the portal venous blood as well as in triglyceride (TG)-rich very low-density lipoproteins (VLDL) in the systemic circulation of healthy individuals, indicating that both dietary and microbial LPS is consistently absorbed through the intestinal epithelia [x].

All gram-negative bacteria have LPS, a necessary part of their outer membrane and a virulence factor. Depending on the organism, LPS has a distinct chemical makeup with varying biologic activity and potency. The repetitive oligosaccharide side chains, the core phosphorylated oligosaccharide, and the lipid A—or endotoxin—backbone are the three primary domains of LPS [x].

1.2 Adhesins
Bacteria have developed methods to colonize surfaces to obtain nutrients, attack host cells, or form defense groups known as biofilms.

Pseudomonas aeruginosa is an example of an opportunistic pathogen that may enter the human host and successfully colonize mucosal surfaces.  P. aeruginosa has two modes of attack: a free-living cytotoxic state that triggers an acute inflammatory response and a biofilm state that results in persistent infections that are resistant to treatment. 

P. aeruginosa must adhere to respiratory, digestive, or urogenital mucosa, infect the underlying cell layers, and finally disseminate to distant tissue sites to prevent nutritional exhaustion and to evade local immune monitoring in order to reside on host tissues [x] successfully.

Using its powerful binding components known as adhesins such as flagella, pili, and biofilms, Pseudomonas aeruginosa are widespread in both natural and artificial settings. P. aeruginosa may survive in various surfaces, including medical equipment and even domestic sink drains [x].

Alginate functions as an adhesin by adhering to mucus present in the respiratory system. Its acetyl groups promote viscosity, which causes water and nutrients to collect in the biofilm. By shielding P. aeruginosa from phagocytosis and scavenging reactive oxygen species generated by activated macrophages, alginate also aids in the persistence of the bacteria. Alginate also triggers a potent leukocyte response, which releases reactive oxygen species and aids in the development of lung inflammation. Alginate also has the ability to bind aminoglycoside antibiotics, preventing them from penetrating the biofilm and increasing antibiotic resistance and treatment failure [x]
Flagella serve a variety of purposes, including bacterial adhesion and movement. They can also activate the inflammatory response in the host via the Toll-like receptor 5 (TLR5). [x]

Administration of human monoclonal antibodies (MAbs) against flagella provided infection protection and reduced lung damage in a rat model of P. aeruginosa-induced pneumonia [x].
LectinsAdhesion is a crucial aspect of pathogenicity.  Successful bacterial attachment to the target surface results in colonization, invasion, and biofilm formation.  
Lectins are sugar-binding proteins that may attach to glycoproteins released from cells as well as to carbohydrates that are present on their surfaces [x]

LecA and LecB are the two main lectins found in P. aeruginosa. These lectins have a variety of functions, including assisting in the creation of biofilms, and are widely distributed on the surface of P. aeruginosa [x,x,x,x]. LecA and LecB must engage with their respective receptors on the target surfaces (such as epithelial cells).  LecA binds to D-galactose or N-acetyl-D-galactosamine, while lecB binds to L-fucose or mannose [x].

LecA damages the respiratory epithelium and has an impact on intestinal epithelial penetration, which increases the absorption of additional virulence factors such as exotoxin A [x] while lecB also contributes to protease IV activity and pilus biogenesis [x , x]
Type IV Pili (TFP) Type IV pilus (TFP) are strong, flexible filamentous appendages expressed on the surface of gram-negative bacteria with varied roles in bacterial pathogenicity [x].
The TPF plays a role in both bacterial movement, such as social gliding motility and microbial adhesion in P. aeruginosa.  Although the form and structure of pili vary, the majority of pili are adhesins that facilitate bacterial interactions with their surroundings or with other cells [x].

1.3 Pigments

Pyoverdine Pyoverdine, a yellow-green, water-soluble fluorescent pigment produced by the Pseudomonas species, is both an effective iron(III) transporter and scavenger. It serves as a simple indicator of bacterial differentiation as a fluorescent pigment. As a siderophore, pyoverdine fulfills the essential nutrient need for iron required for growth in these exclusively aerobic bacteria [x]

Pyoverdine scavenges ferric iron from mammalian iron-sequestering proteins like transferrin by binding ferric iron in a 1:1 stoichiometric ratio with high affinity [x].

Extracting significant amounts of ferric iron from the host results in mitochondrial damage due to compromised electron transfer and ATP production, ultimately activating mitochondrial turnover [x].
Pyocyanin As an antibiotic and antifungal, pyocyanin is an electrochemically active molecule that participates in a number of critical biological processes, such as gene expression, bacterial fitness maintenance, and biofilm formation [x].
Pyorubin Pyorubin and other pigments from P. aeruginosa have been shown in preliminary experiments to have antibacterial activity against other bacteria.  P. aeruginosa is able to adapt and survive in a variety of severe settings, including those with limited nutrition availability, antibiotic treatment, extreme heat, and oxidative stress.  Pyorubin is thought to contribute to the defense against oxidative stress.  [x]
Pyomelanin Pyomelanin plays a role in protection from UV radiation, energy transport, and oxidative stress.  Pyomelanin also plays a significant role in the survival of P. aeruginosa and the development of chronic infection [x]
Phenazine GroupChlororaphin and oxychlororaphin are the other two pigments of the phenazine group besides pyocyanin [x].  In agar media, the chlororaphin crystallizes in a green hue and is insoluble in water [x]. Oxychlororaphin, on the other hand, is water soluble and appears orange [x]

Another  P. aeruginosa pigment that contributes to the orange hue of the culture media is phenazine 1-carboxylate.  By converting Fe(III) to ferrous iron [Fe(II)], phenazine-1-carboxylic acid (PCA), P. aeruginosa is able to overcome Fe(III) limitation [x].

Carboxylic acid can suppress the growth of Mycobacterium avium and Bacillus anthracis and have a bactericidal effect against Staphylococcus aureus [x]

1.4 Toxins

Exotoxin AExotoxin A, produced during P. aeruginosa infections is thought to cause illness by preventing the creation of proteins, having direct cytotoxic effects, and interfering with the host’s cellular immune system.  Exotoxin A antibodies offer a defense against some of the fatal, metabolic, and pathological effects of experimental and clinical pseudomonas infections [x]

Exotoxin A-derived toxoid is now being tested as a vaccine for potential use in immunoprophylaxis against human pseudomonas disease [x].
Exotoxin SExoS, a cytotoxic and antiphagocytic toxin produced by Pseudomonas aeruginosa, is secreted by the type III secretion system (T3SS), and promotes intracellular persistence through its ADP-ribosyltransferase (ADPr) activity [x]
Cell death is initiated when P. aeruginosa reaches the cytosol of epithelial cells independently of T3SS effector toxins, whereas ExoS activity postpones this to allow ongoing intracellular survival and reproduction [x].
Leukocidin (Cytotoxin) Leukocidin (Cytotoxin), as the name implies, is a β-pore-forming toxin that causes lethal morphological changes such as permeability in leukocytes and is associated with increased virulence of P. Aeruginosa [x].  
EnterotoxinThe injection of P. aeruginosa demonstrated the capacity of this organism to cause fluid accumulation in the animal model, and was distinctly different from other toxins [x] .

1.5 Enzymes

Phospholipase C (PLC) Previous research has demonstrated that intratracheal treatment of PLA2 causes immediate lung damage and that respiratory failure linked to conditions like acute pancreatitis correlates well with elevated levels of phospholipase A2 (PLA2) in lung lavages [x].

It has been demonstrated that bacteria like Pseudomonas release phospholipase C. (PLC). P. aeruginosa invasion involves the heat-labile hemolysin phospholipase C (PLC). Phosphorylcholine, one of the essential elements of lung surfactant, is disrupted by the PLC [x].

PLC and PLA2 have the potential to disrupt surfactant function severely and may play a significant role in various types of lung injury even at relatively low doses.  concentrations [x].
RhamnolipidAmphipathic molecules called rhamnolipids are present in the extracellular space. They are secondary metabolites created when rhamnose is joined to O-glycosidic by a dimer of a -hydroxy fatty acid bond. Rhamnolipids can break down lung surfactants and lead to the degradation of tight junctions of respiratory cells [x]

Due to their surfactant qualities, rhamnolipids enable sliding motility in the absence of flagella and swarming movement by lowering surface tension [x].
Rhamnolipids are produced in conditions of iron restriction [x].
LasB ProteaseLasB is a thermolysin-like elastic metalloproteinase and major virulence factor of Pseudomonas aeruginosa [x].

Although LasB has been implicated in P. aeruginosa biofilm formation, its primary function is to promote bacterial colonization [x]

LasB expression spikes during colonization, particularly in the lungs. As a result, it directly contributes to ventilator-associated pneumonia and triggers an inflammatory reaction. The extremely high toxicity of lasB affects the pulmonary immune system.  LasB can interfere with tight junctions, which causes the breakdown of endothelium and epithelial barriers. 

Further, lasB can interfere with tight junctions, which causes the breakdown of endothelium and epithelial barriers, causing tissue damage. 
LasA Protease

LasA, also known as staphylolysin, is a zinc metallopeptidase generated by Pseudomonas aeruginosa. It is the only bacterial peptiglycan hydrolase that has been investigated as a potential staphylolytic agent outside lysostaphin. [x

LasA functions as an elastase and is secreted into the extracellular environment, where it causes the breakdown of elastin [x].

LasA is a member of this endopeptidase family that is a physically distinct crystal structure. The active site of uncomplexed LasA contains two metal-bound water molecules and a five-coordinate zinc ion with trigonal bipyramidal shape [x].

Alkaline ProteaseA zinc metalloprotease also known as AprA, alkaline protease, is inhibited by chelating agents [x]. It typically causes tissue injury and interferes with epithelial cells’ respiratory system, which can disrupt the movement of the cilia. 

Alkaline protease also has a significant function in immune system suppression [x] C1q, and C3 complement components, cytokines, TNF, and IFN are all degraded by AprA. Research also shows that AprA also blocks lectin and classical pathways, stopping the complement process as well [x].

1.6 Metallothioniens

Pathogenic bacteria increase their capacity to harm host tissues and cause diseases by using a variety of virulence factors, including metallothioneins. Pseudomonas aeruginosa produces PMTA, a member of the metallothionein (MT) protein family with expressing a small molecular weight and high cysteine content. The maintenance of healthy levels of zinc and copper, defense against oxidative stress, and the capacity to alter a range of immunological actions are all dependent on MTs.

Pyocyanin, a virulence factor of p. aeruginosa, depends on PmtA expression[x].

Thus, the acquisition of zinc is essential for P. aeruginosa’s virulence, and capacity to colonize environmental and host niches [x].  

In an animal study, zinc sulfate was used to inhibit Pseudomonas protease and was found to reduce corneal perforations better than cysteine and disodium edetate (EDTA).  Paradoxically, zinc sulfate ultimately resulted in greater destruction in the corneas compared with controls, precluding its viability as a treatment option [x]

2. Toxin-Antitoxin System Functions

Biofilm FormulationExopolysaccharide alginate is one of the key elements of the biofilm in P. aeruginosa mucoid strains [x].

P. aeruginosa biofilm production has been demonstrated to depend on bacterial cell communication. The quorum sensing (QS) bacterial cell-to-cell communication system controls the virulence genes in P. aeruginosa [x]

3. P. Aeruginosa Associated Infections 

The main risk factors for P. aeruginosa infections are structural lung disorders, hematological neoplasms, transplantation, skin burns, recent antibiotic usage, presence of implants, prolonged hospitalization, and mechanical ventilation [x]

Pseudomonas Aeruginosa also plays a major role in the Microbiome Signature of serious diseases such as Cystic Fibrosis (CF) and Multiple Sclerosis (MS)

Infections Notes
Cystic FibrosisPseudomonas aeruginosa is one of the most significant bacterial infections encountered by immunocompromised hosts and cystic fibrosis (CF) patients [x], and is the leading cause of mortality [x].
The lipopolysaccharide (LPS) is a critical element in virulence and both innate and acquired host responses to P. aeruginosa infection [x].
It has been hypothesized that P. aeruginosa causes a chronic biofilm-type infection in the CF lung [x].

Controlling bacterial growth by reducing ferric iron Fe(III) uptake has received a lot of interest [x], especially in the context of chronic biofilm-type infections like Cystic Fibrosis [x].

Iron is not only necessary for the growth of P. aeruginosa but iron levels above those needed for growth also encourage the creation of biofilms by indicating a change from a motile to a sessile condition.  P. aeruginosa becomes considerably more resistant to antimicrobials and challenging to remove as a biofilm, which causes a flurry of issues that impair appropriate lung functioning and frequently result in the morbidity and mortality of CF patients [x]

4. Potentially Effective P. Aeruginosa Interventions 

With the rise of antibiotic-resistant bacterial strains, the treatment choices for bacterial infections have become extremely restricted, and the search for a novel general antibacterial therapy has garnered much more attention. 

Pseudomonas aeruginosa is considered a model organism for studying biofilm formation and is the most studied quorum sensing (QS) microorganism [x].  A quorum quenching (QS) strategy interferes with the quorum sensing (QS) mechanism of P. aeruginosa and aims to restrict cell development and communication of the pathogen, representing a novel alternative to conventional antibiotics [x].

4.1 Probiotics

4.2 Monoclonal antibody therapy 

4.3 Whole bacteria and bacterial lysates 

4.4  Vaccines

4.5 Supplements

Pseudomonas Aeruginosa Summary

•Pseudomonas aeruginosa is a prominent bacterial pathogen that has become one of the most frequent causes of nosocomial infections in recent years due to contemporary medical treatments.

• Virulence factors like lipopolysaccharides, adhesins, pigments and toxins allow P. aeruginosa to colonize host tissues and cause infection.

• Lipopolysaccharide (LPS) consists of three primary domains: repetitive oligosaccharide side chains, core phosphorylated oligosaccharide, and lipid A—or endotoxin—backbone which aid in virulence development and survival.

• Adhesins such as flagella pili help with microbial adhesion while alginate helps form biofilms by binding aminoglycosides antibiotics thus increasing antibiotic resistance levels against treatment failure .

• Pigments like pyoverdine are effective iron(III) transporters while pyocyanin acts as an antibiotic & antifungal agent; phenazine group aids protection from UV radiation & oxidative stress; Pyomelanin plays role in energy transport & defense against oxidative stress .  Toxins such as exotoxin A prevent creation proteins directly

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