Abstract
Pseudomonas aeruginosa is a metabolically versatile opportunistic pathogen capable of surviving in a range of environments. The major contribution to these abilities relies on virulence factor production, e.g., exotoxins, phenazines, and rhamnolipids, regulated through a hierarchical system of communication, named quorum sensing (QS). QS involves the production, release, and recognition of two classes of diffusible signal molecules: N-acyl-homoserine lactones and alkyl-quinolones. These present a central role during P. aeruginosa infection, regulating bacterial virulence and the modulation of the host immune system. The influence of this arsenal of virulence factors on bacterial–host interaction makes P. aeruginosa a highly potential platform for the development of biopharmaceuticals. Here, we comprehensively reviewed the therapeutical applications of P. aeruginosa virulence factors and quorum sensing signaling molecules on pathological conditions, ranging from infections and inflammation to cancer disease.
Key Points
- Quorum Sensing and Virulence Regulation: P. aeruginosa employs quorum sensing (QS) to regulate virulence factor production. QS molecules such as N-acyl-homoserine lactones and alkyl-quinolones play a central role in bacterial communication, host immune modulation, and potential drug development.
- Phenazines as Antimicrobials and Immunomodulators: Phenazine derivatives, such as pyocyanin, exhibit antimicrobial, anti-inflammatory, and antitumor properties. These compounds modulate oxidative stress, inhibit pro-inflammatory cytokines, and demonstrate cytotoxic activity against cancer cells.
- Exotoxin A as a Basis for Immunotoxins: Exotoxin A, a major virulence factor of P. aeruginosa, has been engineered into recombinant immunotoxins. Moxetumomab pasudotox, an FDA-approved immunotoxin, targets hematologic cancers, and research is ongoing to adapt these molecules for solid tumor treatment.
- Rhamnolipids in Wound Healing and Cancer Therapy: Rhamnolipids (RLs), biosurfactants produced by P. aeruginosa, exhibit antimicrobial activity, biofilm inhibition, and wound healing properties. Additionally, RLs selectively target cancer cells through membrane disruption and apoptosis induction, making them promising candidates for oncological applications.
- Aeruginaldehyde as an Antimicrobial and Antitumor Agent: Aeruginaldehyde, a secondary metabolite of P. aeruginosa, demonstrates antifungal, immunomodulatory, and cytotoxic properties. Its ability to induce apoptosis and regulate oxidative stress suggests potential applications in infectious disease management and cancer therapy.
- Potential of Alkyl-Quinolones in Drug Development: Alkyl-quinolones, key components of P. aeruginosa’s QS system, have demonstrated antimicrobial and immunomodulatory effects. These molecules interfere with host immune signaling and could serve as novel anti-inflammatory agents.
- Biotechnological Applications of P. aeruginosa: The bacterium’s extensive biosynthetic capacity enables its use in industrial applications, such as producing bioactive molecules for pharmaceuticals, cosmetics, and agriculture. Advances in synthetic biology and metabolic engineering could further enhance its potential.
- Challenges in Therapeutic Development: Despite promising bioactivities, P. aeruginosa-derived compounds face challenges such as cytotoxicity, immunogenicity, and regulatory hurdles. Strategies to reduce toxicity and enhance selective targeting are critical for clinical translation.
- Future Directions in Drug Discovery: Research into novel P. aeruginosa-derived compounds, combined with advances in nanotechnology and drug delivery systems, could lead to next-generation antimicrobial, immunotherapeutic, and anticancer agents.
- Clinical and Regulatory Considerations: The translation of P. aeruginosa-derived molecules into viable therapeutics requires rigorous preclinical and clinical evaluations. Regulatory frameworks must address concerns regarding bacterial virulence and potential biosafety risks.
