Antimicrobial activity of novel 4H-4-oxoquinolizine compounds against extensively drug-resistant Acinetobacter baumannii strains

Seok HyeonNa, HyejinJeon, Yoo JeongKim, Hyo IlKwon, Gati NobleSelasi, AsiimweNicholas, Chang-SooYun, Sang HoLee, Je ChulLee

Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, South Korea.

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 50µg/mL, which was >32.5- to 119-fold higher than the MIC₉₀ for 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.

Keywords: 4H-4-oxoquinolizine, Fluoroquinolone, Antimicrobial resistance, DNA gyrase inhibitor, Chemical compound.