title: Antimicrobial activity of novel 4H-4-oxoquinolizine compounds against extensively drug-resistant Acinetobacter baumannii strains.
abstract: The aim of this study was to screen lead compounds exhibiting potent in vitro antimicrobial activity against multidrug-resistant (MDR) Acinetobacter baumannii strains from a library of chemical compounds. In a high-throughput screening analysis of 7520 compounds representative of 340,000 small molecules, two 4H-4-oxoquinolizine compounds were the most active against A. baumannii ATCC 17978. Subsequent selection and analysis of 70 4H-4-oxoquinolizine compounds revealed that the top 7 compounds were extremely active against extensively drug-resistant (XDR) A. baumannii isolates. These compounds commonly carried a 1-cyclopropyl-7-fluoro-4-oxo-4H-quinolizine-3-carboxylic acid core structure but had different C-8 and/or C-9 moieties. Minimum inhibitory concentrations (MICs) of the seven compounds against fluoroquinolone-resistant A. baumannii isolates were found to be in the range of 0.02-1.70 µg/mL regardless of the mutation types in the quinolone resistance-determining region (QRDR) of GyrA and ParC. Cytotoxicity of the seven compounds was observed in HeLa and U937 cells at a concentration of 50 µg/mL, which was >32.5- to 119-fold higher than the MIC90for A. baumannii isolates. In conclusion, novel 4H-4-oxoquinolizine compounds represent a promising scaffold on which to develop antimicrobial agents against drug-resistant A. baumannii strains.
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.
authors.forename: Seok Hyeon
authors.initials: SH
authors.lastname: Na
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Jeon
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.
authors.forename: Yoo Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.
authors.forename: Hyo Il
authors.initials: HI
authors.lastname: Kwon
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.
authors.forename: Gati Noble
authors.initials: GN
authors.lastname: Selasi
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.
authors.forename: Asiimwe
authors.initials: A
authors.lastname: Nicholas
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Yun
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea. Electronic address: leejc@knu.ac.kr.
authors.forename: Je Chul
authors.initials: JC
authors.lastname: Lee
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D008826:Microbial Sensitivity Tests; D011807:Quinolizines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D011807:Quinolizines
keywords: 4H-4-oxoquinolizine; Antimicrobial resistance; Chemical compound; DNA gyrase inhibitor; Fluoroquinolone