Design, synthesis and biological evaluation of novel 3-hydroxypyridin-4(1H)-ones based hybrids as Pseudomonas aeruginosa biofilm inhibitors

• Published in: European journal of medicinal chemistry 2023-11, Vol.259, p.115665-115665, Article 115665
• Main Authors: Liu, Jun, Meng, Ying, Yang, Ming-Han, Zhang, Xiao-Yi, Zhao, Jian-Fu, Sun, Ping-Hua, Chen, Wei-Min
• Format: Article
• Language: English
• Subjects: 3-Hydroxypyridin-4(1H)-one; Biofilm inhibitor; Las pathway; Pqs pathway; Pseudomonas aeruginosa; Quorum sensing
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115665

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative pathogenic bacterium, often causative drug-resistance related human infections, given its great capacity to form bioflm. It uses three major quorum sensing (QS) systems, las, rhl, and pqs, to regulate the expression of genes related to virulence and biofilm formation. Consequently, strategies for inhibiting QS have garnered considerable attention as antimicrobial therapies. In this study, we designed and synthesized several 3-hydroxypyridin-4(1H)-one hybrids and assessed their potential as the inhibitors of P. aeruginosa biofilm formation. The most active compound identified was 12h; it exhibited satisfactory biofilm inhibitory activity (IC50: 10.59 ± 1.17 μM). Mechanistic studies revealed that 12h significantly inhibited the fluorescence of the PAO1-lasB-gfp and PAO1-pqsA-gfp fluorescent reporter strains and the production of Las-regulated (elastase) and Pqs-regulated (pyocyanin) virulence factors. These findings indicate that 12h inhibited biofilm formation by suppressing the expression of lasB and pqsA, thereby inactivating the las and pqs pathways. Furthermore, 12h improved the antibiotic susceptibility of P. aeruginosa and reduced the acute virulence of this bacterium in the African green monkey kidney cell line Vero. In conclusion, 3-hydroxypyridin-4(1H)-one hybrids, such as 12h, represent a promising class of antibacterial agents against P. aeruginosa. [Display omitted] •A series of 3-hydroxypyridin-4(1H)-ones-based hybrids were synthesized.•Compound 12h with excellent biofilm inhibitory activity was identified.•12h inhibits the bacterial biofilm formation by inhibiting bacterial lasB, and pqsA.•12h exhibits synergy with antibiotics against multidrug-resistant P. aeruginosa.