title: Long-Chain 4-Aminoquinolines as Quorum Sensing Inhibitors in Serratia marcescens and Pseudomonas aeruginosa.
abstract: Antibiotic resistance has become a serious global threat to public health; therefore, improved strategies and structurally novel antimicrobials are urgently needed to combat infectious diseases. Here we report a new type of highly potent 4-aminoquinoline derivatives as quorum sensing inhibitors in Serratia marcescens and Pseudomonas aeruginosa, exhibiting weak bactericidal activities (minimum inhibitory concentration (MIC) > 400 μM). Through detailed structure-activity study, we have identified 7-Cl and 7-CF3substituted N-dodecylamino-4-aminoquinolines (5 and 10) as biofilm formation inhibitors with 50% biofilm inhibition at 69 μM and 63 μM in S. marcescens and P. aeruginosa, respectively. These two compounds, 5 and 10, are the first quinoline derivatives with anti-biofilm formation activity reported in S. marcescens. Quantitative structure-activity relationship (QSAR) analysis identified structural descriptors such as Wiener indices, hyper-distance-path index (HDPI), mean topological charge (MTC), topological charge index (TCI), and log D(o/w)expas the most influential in biofilm inhibition in this bacterial species. Derivative 10 is one of the most potent quinoline type inhibitors of pyocyanin production described so far (IC50= 2.5 μM). While we have demonstrated that 5 and 10 act as Pseudomonas quinolone system (PQS) antagonists, the mechanism of inhibition of S. marcescens biofilm formation with these compounds remains open since signaling similar to P. aeruginosa PQS system has not yet been described in Serratia and activity of these compounds on acylhomoserine lactone (AHL) signaling has not been detected. Our data show that 7-Cl and 7-CF3substituted N-dodecylamino-4-aminoquinolines present the promising scaffolds for developing antivirulence and anti-biofilm formation agents against multidrug-resistant bacterial species.
authors.affiliation: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Vojvode Stepe 444a, P.O. Box 23, 11010 Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Aleksić
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, University of Belgrade , Njegoševa 12, P.O. Box 473, 11000 Belgrade, Serbia.
authors.forename: Sandra
authors.identifier: 0000-0003-1204-5487
authors.initials: S
authors.lastname: Šegan
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, University of Belgrade , Njegoševa 12, P.O. Box 473, 11000 Belgrade, Serbia.
authors.forename: Filip
authors.identifier: 0000-0001-7932-833X
authors.initials: F
authors.lastname: Andrić
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 12-16, P.O. Box 51, 11158 Belgrade, Serbia.
authors.forename: Mario
authors.identifier: 0000-0003-4311-1731
authors.initials: M
authors.lastname: Zlatović
authors.affiliation: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Vojvode Stepe 444a, P.O. Box 23, 11010 Belgrade, Serbia.
authors.forename: Ivana
authors.identifier: 0000-0001-6731-7115
authors.initials: I
authors.lastname: Moric
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, University of Belgrade , Njegoševa 12, P.O. Box 473, 11000 Belgrade, Serbia.
authors.forename: Dejan M
authors.identifier: 0000-0002-5948-0702
authors.initials: DM
authors.lastname: Opsenica
authors.affiliation: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Vojvode Stepe 444a, P.O. Box 23, 11010 Belgrade, Serbia.
authors.forename: Lidija
authors.identifier: 0000-0002-6965-9407
authors.initials: L
authors.lastname: Senerovic
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D053038:Quorum Sensing / Q000187:drug effects*; D012706:Serratia marcescens / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; C001920:4-aminoquinoline