Hydroquinine Inhibits the Growth of Multidrug-Resistant Pseudomonas aeruginosa via the Suppression of the Arginine Deiminase Pathway Genes

Weawsiangsang, Sattaporn; Rattanachak, Nontaporn; Jongjitvimol, Touchkanin; Jaifoo, Theerasak; Charoensit, Pensri; Viyoch, Jarupa; Ross, Sukunya; Ross, Gareth; Baldock, Robert A.; Jongjitwimol, Jirapas

doi:10.3390/ijms241813914

Published September 10, 2023 | Version v1

Publication Open

Hydroquinine Inhibits the Growth of Multidrug-Resistant Pseudomonas aeruginosa via the Suppression of the Arginine Deiminase Pathway Genes

1. Biomedical Sciences Program, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
2. Pibulsongkram Rajabhat University
3. Master of Science in Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
4. Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
5. Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok 65000, Thailand
6. Biopolymer Group, Department of Chemistry, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand
7. Centre of Excellence in Biomaterials, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand
8. School of Pharmacy and Biomedical Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth PO1 2DT, UK

Hydroquinine has antimicrobial potential with demonstrated activity against several bacteria, including multidrug-resistant (MDR) P. aeruginosa reference strains. Despite this, there is limited evidence confirming the antibacterial activity of hydroquinine against clinical isolates and the underlying mechanism of action. Here, we aimed to investigate the antibacterial effect of hydroquinine in clinical P. aeruginosa strains using phenotypic antimicrobial susceptibility testing and synergistic testing. In addition, we examined the potential inhibitory mechanisms against MDR P. aeruginosa isolates using informatic-driven molecular docking analysis in combination with RT-qPCR. We uncovered that hydroquinine inhibits and kills clinical P. aeruginosa at 2.50 mg/mL (MIC) and 5.00 mg/mL (MBC), respectively. Hydroquinine also showed partial synergistic effects with ceftazidime against clinical MDR P. aeruginosa strains. Using SwissDock, we identified potential interactions between arginine deiminase (ADI)-pathway-related proteins and hydroquinine. Furthermore, using RT-qPCR, we found that hydroquinine directly affects the mRNA expression of arc operon. We demonstrated that the ADI-related genes, including the arginine/ornithine antiporter (arcD) and the three enzymes (arginine deiminase (arcA), ornithine transcarbamylase (arcB), and carbamate kinase (arcC)), were significantly downregulated at a half MIC of hydroquinine. This study is the first report that the ADI-related proteins are potential molecular targets for the inhibitory effect of hydroquinine against clinically isolated MDR P. aeruginosa strains.

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We thank all of the research funders. This work was partially supported by the Global and Frontier Research University Fund, Naresuan University, grant number R2566C052, and the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 871650. We would like to acknowledge the Faculty of Allied Health Sciences, Naresuan University; the Faculty of Science and Technology, Pibulsongkram Rajabhat University; and the Department of Medical Technology and Clinical Pathology, Kamphaeng Phet Hospital for supporting all facilities.

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