Sima Golmakaniyoon - Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Mehran Ghanei - School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Bibi Sedigheh Fazly Bazzaz - Department of Pharmaceutical Control, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Razieh Ghodsi - Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Vahid Soheili - Department of Pharmaceutical Control, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Introduction and Objectives: Increasing antibiotic resistance requires immediate novel therapeutic decisions to battle microbial infections. One of the alternative approaches to overcome resistance is intervening with the bacterial pathogenicity without affecting the cell viability. Here, we selected PqsR, one of the virulence regulator proteins of Pseudomonas aeruginosa, as an attractive target in its quorum-sensing network. Materials and Methods: Based on the reported antimicrobial effects of Henna (Lawsonia inermis), and the chemical structure relationship of Lawsone and PqsR ligand, a series of Lawsone derivatives were synthesized to assess against P. aeruginosa PAO1. After determination of MIC (Minimum Inhibitory Concentration) values, one of the compounds was selected and evaluated against biofilm formation, virulence factors production (including pyocyanin, pyoverdine and protease), acyl homoserine lactones (AHLs) accumulation, and Tobramycin effectiveness potentiation. Additionally, its interaction with the active site of PqsR was studied by molecular modeling. Results: The results indicated that the selected compound can be used as a potential inhibitor in preventing biofilm formation and virulence factors production which are important factors in antibiotic resistance. It is also a good candidate to increase Tobramycin potency against P. aeruginosa. Conclusion: This study presents a novel insight into ligand-based drug design and affords a chemical scaffold to inhibit P. aeruginosa pathogenicity by targeting PqsR.

Pseudomonas aeruginosa, PqsR, Lawsonia inermis, Lawsone, Biofilm