Screening of Potential Blockers of Pseudomonas aeruginosa Third Quorum Sensing System; Pseudomonas quinolone signal (PQS)

Quorum sensing system (QS) is a process by which regulation of certain genes expression can occur in response to exceeding cell density threshold. This sort of communication depends on the secretion of small diffusible molecules called autoinducers (AIs), in which they bind to specific receptors to act as a DNA binding complex and increase the expression of multiple genes related to virulence and antibiotic resistance. Pseudomonas aeruginosa is a very common opportunistic pathogen in our environment and can cause severe complications and often death, especially in immunocompromised patients such as cystic fibrosis patients. Moreover, Pseudomonas aeruginosa is a well know multidrug-resistant microorganism, in which the idea of developing new antibiotics is a challenge because it comprises a temporary solution due to resistance. Therefore, our aim is to tackle this problem by acting on the QS system, because it will not eliminate the bacteria, hence, the resistance probability will be minimized. Pseudomonas aeruginosa has 4 main QS systems, Las, Rhl, Pqs, and Iqs, that are highly interconnected together. Our work mainly focused on the Pseudomonas quinolone signal PQS system, which depends on quinolone-based autoinducers. PQS system is responsible for the regulation of many virulence factors, such as pyocyanin, elastase, efflux pumps for antibiotics, siderophores, hydrogen cyanide, biofilm, and many more. Consequently, the inhibition of this system is a rational approach. Thus, we performed multiple assays of 8 chemically synthesized quinolone derivatives to assess their efficacy in diminishing the bacterium virulence through PQS blockage. One of the 8 compounds, compound 4, showed slightly positive feedback in certain assays, however, the majority did not show any effect. In silico molecular docking was used to further explain these results, which enabled us to clearly see the difference between these compounds in terms of structure, size, binding residues, and interaction type. As a final proposal, we can anticipate obtaining better efficacy toward this system through a series of lead optimization strategies, especially on compound 4.