Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1H)-ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa

Abstract

2-Heptyl-3-hydroxy-4­(1H)-quinolone (PQS), a compound from P. aeruginosa, functions as both a quorum sensing (QS) regulator and a potent iron chelator to induce expression of pyoverdine and pyochelin which are involved in high-affinity iron transport systems. A potential dual-acting antibiofilm strategy requires molecules designed to interfere with iron uptake and the QS system of P. aeruginosa. A series of 2-substituted 3-hydroxy-1,6-dimethylpyridin-4-ones have been designed, synthesized, and tested as biofilm inhibitors of P. aeruginosa. One compound, N-((1,3,6-trimethyl-4-oxo-1,4-dihydropyridin-2-yl)­methyl)­hexanamide (10d), exhibits 68.67% biofilm inhibitory activity at 20 μM. Further mechanistic studies have confirmed that this compound not only inhibits the QS systems of P. aeruginosa but also acts as an iron chelator to compete strongly with pyoverdine, causing iron deficiency in bacteria. The pyoverdine receptor FpvA was revealed as the target of 10d by the Pvds mutant strain, fpvA-overexpressed strain, and in silico studies.

Oxygen Self-Supplying Nanotherapeutic for Mitigation of Tissue Hypoxia and Enhanced Photodynamic Therapy of Bacterial Keratitis

“…aeruginosa biofilm, three kinds of motilities including swarming, swimming, and twitching motility are correlated with the bacterial colonization. As a representative, twitching motility plays a major role in the biofilm formation . Hence, the twitching motility was quantified by measuring the twitching distance, as previously described .…”

“…As a representative, twitching motility plays a major role in the biofilm formation. 25 Hence, the twitching motility was quantified by measuring the twitching distance, as previously described. 26 Briefly, 2 mL of PBS, pGF-I, or PFH/F-I was mixed with 20 mL of medium supplemented with 1% (w/v) Bacto Agar, 0.5% (w/v) casamino acids, and 0.5% (w/ v) glucose, respectively.…”

Prevalence of antibiotic resistance and virulent factors in nosocomial clinical isolates of Pseudomonas aeruginosa from Panamá

“…by combining iron-chelators with antibiotics, given the preponderant physiological role of iron in the physiology of this pathogen. 42 , 49 , 50 , 51 , 52 The virulence factors identified in our study provides valuable information regarding the prevalence of resistance genes and their potential impact on treatments that exploit the unique physiology of the pathogen. More importantly, this information can be used to better guide future control strategies, understand the evolution and dissemination of strains hoping to prevent the development of resistance in Pseudomonas aeruginosa.…”

Quorum Sensing Inhibitors to Quench P. aeruginosa Pathogenicity

“…This derivative showed an anti-pyocyanin activity (IC 50 of 3.65 µM in a P. aeruginosa PA14 strain) similar to the one of compound 41. The pyranone and pyridinone derivatives 42 and 43 described by Li et al were both able to inhibit biofilm formation without affecting bacterial growth with IC50s of 20.3 and 6.57 µM in a P. aeruginosa PAO1 strain, respectively (Scheme 10, Table 4) [117,118]. The compound 42 also revealed an anti-pyocyanin activity with 60% inhibition at 40 µM.…”