Pseudomonas aeruginosa Quorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives

Abstract

Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multidrug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to coordinate virulence gene expression, is a potential target that has been intensively investigated over the past decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems ( las, rhl, and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.

Dual bioresponsive antibiotic and quorum sensing inhibitor combination nanoparticles for treatment of Pseudomonas aeruginosa biofilms in vitro and ex vivo

“…Since bacterial communities coordinate their pathogenic activities including biofilm development through cell-cell communication (quorum sensing, QS) 5,18 using small diffusible signal molecules, disruption of QS interferes with biofilm formation and maturation. [19][20][21][22][23] However, while there are combination formulations in the clinic which use antibiotics and β-lactamase inhibitors (e.g. Tazocin®, Unasyn® Augmentin®), none to date have utilised QS inhibitors (QSIs) as biofilm disrupting agents.…”

Membrane-Interactive Compounds fromPistacia lentiscusL. ThwartPseudomonas aeruginosaVirulence

“…28,29 These new therapies target essentially the prevention of virulence factors production by pathogens, rather than their survival, and they also aim to thwart the regulatory mechanisms controlling their expression. 19,30 In addition, by targeting essential virulence determinants, the emergence and spread of bacterial resistance will be reduced due to decreased selective pressure and the natural microbiota will be preserved. In line with this scenario, the current study was designed to explore new anti-virulence agents to fight against the multidrug-resistant P. aeruginosa that is responsible for many different infections.…”

“…Since for P. aeruginosa infections QS is the master regulator involved in the expression of many virulence factors such as phenazines, exoproteases (elastase, alkaline protease), siderophores, and toxins among others, its inhibition represents a valuable adjuvant therapy that might be used to potentiate the activity of the available antibiotics applied to handle early P. aeruginosa infections. 19,30 In the last five years there was a large amount of published investigations reporting natural products highlighting their potential in targeting bacterial virulence factors. 21 Several plant-derived compounds that belong to alkaloids, organosulfurs, coumarins, flavonoids, phenolic acids, phenylpropanoids, terpenoids among other chemical classes have been found to be active against pyocyanin pigment production.…”

“…In view of this, developing anti-virulence agents that may precisely hinder the production, secretion, or function of virulence determinants or interfere with their regulation has emerged as an alternative promising strategy to fight against bacterial pathogens. 18,19 Plants have long been used in traditional medicine to prevent or treat infectious diseases in many countries. 20 Hydrophilic and lipophilic extracts from plants were reported to contain abundant and diverse range of bioactive compounds with anti-virulence properties.…”

“…20 Hydrophilic and lipophilic extracts from plants were reported to contain abundant and diverse range of bioactive compounds with anti-virulence properties. 19,21,22 Pistacia lentiscus L., a plant commonly known as mastic tree or lentisc, is an evergreen shrub of the family of Anacardiaceae widespread all around the Mediterranean area where it grows wild in a variety of ecosystems. 23,24 Medicinal uses of the fruit, galls, resin, and leaves of P. lentiscus L. Are described since antiquity.…”