title: Structure-Activity Relationships of 2-Sufonylpyrimidines as Quorum-Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa.
abstract: Drug-resistant Pseudomonas aeruginosa (PA) strains are on the rise, making treatment with current antibiotics ineffective. Hence, circumventing resistance or restoring the activity of antibiotics by novel approaches is of high demand. Targeting the Pseudomonas quinolone signal quorum sensing (PQS-QS) system is an intriguing strategy to abolish PA pathogenicity without affecting the viability of the pathogen. Herein we report the structure-activity relationships of 2-sulfonylpyrimidines, which were previously identified as dual-target inhibitors of the PQS receptor PqsR and the PQS synthase PqsD. The SAR elucidation was guided by a combined approach using ligand efficiency and ligand lipophilicity efficiency to select the most promising compounds. In addition, the most effective inhibitors were rationally modified by the guidance of QSAR using Hansch analyses. Finally, these inhibitors showed the capacity to decrease biofilm mass and extracellular DNA, which are important determinants for antibiotic resistance.
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E 8.1, 66123, Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Thomann
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E 8.1, 66123, Saarbrücken, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brengel
authors.affiliation: PharmBioTec GmbH, Science Park 1, 66123, Saarbrücken, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Börger
authors.affiliation: PharmBioTec GmbH, Science Park 1, 66123, Saarbrücken, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kail
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E 8.1, 66123, Saarbrücken, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Steinbach
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E 8.1, 66123, Saarbrücken, Germany.
authors.forename: Martin
authors.identifier: 0000-0002-0503-5830
authors.initials: M
authors.lastname: Empting
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E 8.1, 66123, Saarbrücken, Germany.|Saarland University, Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Campus C 2.3, 66123, Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D004269:DNA, Bacterial / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D011743:Pyrimidines
keywords: Hansch analysis; P. aeruginosa; biofilms; drug design; medicinal chemistry; nitrogen heterocycles