Tackling multi-drug resistance in Pseudomonas aeruginosa thanks to a new promising anti-virulence strategy

The emergence and the dissemination of multi-drug resistant bacteria constitute a major public health issue. Among incriminated Gram-negative bacteria (GNB), Pseudomonas aeruginosa has been designated by the WHO as a critical priority threat. This pathogen is responsible for various nosocomial infections, usually lethal for patients suffering from cystic fibrosis. Its ability to establish biofilms reinforces its virulence and intrinsic drug resistance. Its pathogenicity is orchestrated by the Quorum Sensing (QS) that refers to bacterial communication systems. This sophisticated coordination network relies on the secretion and perception of small signalling molecules called autoinducers (AIs). The extracellular concentration of AIs acts as a population density indicator. The biomass growth provokes an increased release of AIs inducing the expression of QS-associated genes via the activation of specific transcription factors. This stimulation ensures the biosynthesis of essential proteins for the synchronisation of bacteria colonies regarding the environmental conditions and especially those implicated in the virulence pathways. Three interconnected QS circuits regulate P. aeruginosa pathogenicity. Taking into account the widespread occurrence of N-acyl-homoserine lactone (AHL)-mediated communication las and rhl systems in GNB, the third species-specific pqs network appears as a pool of promising therapeutic targets for the development of inhibitors. The main AI of this circuit is the 2-heptyl-3-hydroxy-4(1H)-quinolone named Pseudomonas quinolone signal (PQS) that activates the PqsR transcriptional regulator.⁽¹⁾

In the last decades, the interest of a quorum silencing pharmacological approach has emerged. Indeed, the selective pressure put on sensitive bacteria by conventional antimicrobial molecules causing their death promotes resistant strain survival. Non-bactericidal anti-virulence agents (AVAs) could increase pathogen sensibility to the host immune system response in monotherapy. In combination therapy, they could restore the efficiency of current ATBs by inhibiting the formation of the hermetic barrier provided by biofilms.⁽¹⁾ A benzamide-benzimidazole hybrid discovered by Starkey et al. appears as one of the most promising PqsR inhibitor in preclinical stage.⁽²⁾ It revealed the best anti-virulence activity among all reported in literature with efficient anti-pyocyanin and anti-biofilm properties (IC₅₀s of 300 nM and 1 µM, respectively). With this in mind, our team has recently developed a novel family of 2-heteroaryl-4-quinolones as AVAs. The synthesis pathways, but also the physicochemical and biological evaluations of these compounds (intrinsic antibiotic and anti-virulence properties) will be described in the presentation.

References : ⁽¹⁾ Duplantier, M.; Lohou, E.; Sonnet, P. Quorum Sensing Inhibitors to Quench P. aeruginosa Pathogenicity, Pharmaceuticals 2021, 14, 1262; doi:10.3390/ph14121262 ; ⁽²⁾ Starkey, M.; Lepine, F.; Maura, D.; Bandyopadhaya, A.; Lesic, B.; He, J.; Kitao, T.; Righi, V.; Milot, S.; Tzika, A.; et al. Identification of Anti-Virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity, PLoS Pathog. 2014, 10, e1004321, doi:10.1371/journal.ppat.1004321.