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Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1 H )-ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa .
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Oct 08; Vol. 63 (19), pp. 10921-10945. Date of Electronic Publication: 2020 Sep 17. - Publication Year :
- 2020
-
Abstract
- 2-Heptyl-3-hydroxy-4(1 H )-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.
- Subjects :
- Animals
Anti-Bacterial Agents chemistry
Cell Line
Iron metabolism
Iron Chelating Agents chemistry
Iron Chelating Agents pharmacology
Microbial Sensitivity Tests
Pseudomonas aeruginosa growth & development
Pseudomonas aeruginosa metabolism
Pyridones chemistry
Structure-Activity Relationship
Anti-Bacterial Agents pharmacology
Biofilms drug effects
Pseudomonas aeruginosa drug effects
Pyridones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32866008
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c00763