Interference With Quorum-Sensing Signal Biosynthesis as a Promising Therapeutic Strategy Against Multidrug-Resistant Pathogens

Abstract

Faced with the global health threat of increasing resistance to antibiotics, researchers are exploring interventions that target bacterial virulence factors. Quorum sensing is a particularly attractive target because several bacterial virulence factors are controlled by this mechanism. Furthermore, attacking the quorum-sensing signaling network is less likely to select for resistant strains than using conventional antibiotics. Strategies that focus on the inhibition of quorum-sensing signal production are especially attractive because the enzymes involved are expressed in bacterial cells but are not present in their mammalian counterparts. We review here various approaches that are being taken to interfere with quorum-sensing signal production via the inhibition of autoinducer-2 synthesis, PQS synthesis, peptide autoinducer synthesis, and N-acyl-homoserine lactone synthesis. We expect these approaches will lead to the discovery of new quorum-sensing inhibitors that can help to stem the tide of antibiotic resistance.

Naringenin Inhibition of the Pseudomonas aeruginosa Quorum Sensing Response Is Based on Its Time-Dependent Competition With N-(3-Oxo-dodecanoyl)-L-homoserine Lactone for LasR Binding

“…Deepening into the mechanisms of QS inhibition may help in the development of such inhibitors, which have been proposed as suitable anti-infective drugs (Fleitas Martinez et al, 2018). Based in our results, we therefore propose that screenings for QS inhibitors should not only focus on finding molecules with an overall inhibitory effect of virulence phenotypes, but also should analyze their effectiveness over dense populations and select those whose mechanisms of action do not depend on the QS status of populations.…”

Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections

“…The strategies to interfere with quorum sensing are directed against the biosynthesis, accumulation, and detection of the signals derived from small molecules that act as selfinductors of the propagation of quorum sensing (346). Among the strategies to inhibit quorum sensing are the interference with transcriptional factors related to DNA transcription and signal interference of the quorum sensing once it has been detected, as has been applied successfully with P. aeruginosa (347), as well as the inhibition of bacterial enzymes related to this process in different bacteria, including P. aeruginosa (348).…”

Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa

“…The pqs system is crucial for P. aeruginosa pathogenicity and has been regarded as a promising therapeutic target to alleviate antibiotic-resistant infections (Fleitas Martinez et al, 2018). Several attempts to target the pqs system with various PqsR inhibitors have previously been reported (Soukarieh et al, 2018a,b).…”