Quorum Sensing Inhibitors to Quench P. aeruginosa Pathogenicity

Abstract

The emergence and the dissemination of multidrug-resistant bacteria constitute a major public health issue. Among incriminated Gram-negative bacteria, Pseudomonas aeruginosa has been designated by the WHO as a critical priority threat. During the infection process, this pathogen secretes various virulence factors in order to adhere and colonize host tissues. Furthermore, P. aeruginosa has the capacity to establish biofilms that reinforce its virulence and intrinsic drug resistance. The regulation of biofilm and virulence factor production of this micro-organism is controlled by a specific bacterial communication system named Quorum Sensing (QS). The development of anti-virulence agents targeting QS that could attenuate P. aeruginosa pathogenicity without affecting its growth seems to be a promising new therapeutic strategy. This could prevent the selective pressure put on bacteria by the conventional antibiotics that cause their death and promote resistant strain survival. This review describes the QS-controlled pathogenicity of P. aeruginosa and its different specific QS molecular pathways, as well as the recent advances in the development of innovative QS-quenching anti-virulence agents to fight anti-bioresistance.

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

“…Inhibiting Staphylococcus aureus virulence factors also demonstrated attractive effects [ 24 ], such as the inhibition of the agr -mediated quorum sensing system by savirin, which promotes the host defense [ 25 ]. The inhibition of the P. aeruginosa quorum sensing was also reported with promising effects on biofilm development, virulence factor secretion and host colonization [ 26 ]. Among the P. aeruginosa virulence factors, Elastase B (LasB) is considered to be one of the most important [ 27 , 28 ]; its inhibition by small molecules improves the survival rate in mice and Galleria mellonella larvae [ 29 , 30 , 31 , 32 ].…”

Gregatins, a Group of Related Fungal Secondary Metabolites, Inhibit Aspects of Quorum Sensing in Gram-Negative Bacteria

“…It is often reported that inhibition of QS leads to the inhibition of biofilm formation and the production of virulence factors (Duplantier et al, 2021 ). However, in this study, we only find an inhibitory activity of gregatin D on pyocyanin production, while it activates rhamnolipid synthesis and biofilm formation in QS mutants.…”

Recent Advance in Small Molecules Targeting RhlR of Pseudomonas aeruginosa

“…This review describes structure-activity relationship (SAR) studies of RhlR-targeted agonists and antagonists and discusses RhlR-targeted drug opportunities as anti-biofilm agents. The structural relationship of RhlR-targeted modulators (agonists and antagonists) was analyzed by classifying tail, middle, and head sections, inducing detailed SAR studies compared to the previous RhlR studies [ 30 , 31 ]. Furthermore, the importance of developing RhlR modulators for treating patients infected with P. aeruginosa was emphasized under LasR-mutants and phosphate-limiting conditions.…”