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

Int J Mol Sci. 2023 Sep 10;24(18):13914. doi: 10.3390/ijms241813914.

Abstract

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.

Keywords: Pseudomonas aeruginosa; arginine deiminase pathway; drug resistance; hydroquinine.

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Anti-Infective Agents* / metabolism
  • Arginine / metabolism
  • Genes, Bacterial
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Pseudomonas aeruginosa* / metabolism

Substances

  • arginine deiminase
  • hydroquinidine
  • Anti-Infective Agents
  • Anti-Bacterial Agents
  • Arginine

Grants and funding

This research was partially supported by the Asia Research Center, Institute of Asian Studies, Chulalongkorn University (grant number 008/2566 to J.J.). T.J. (Touchkanin Jongjitvimol) thankfully acknowledges funding from Pibulsongkram Rajabhat University (Fundamental Fund: fiscal year 2024). S.W. thankfully acknowledges funding from the Graduate School, Naresuan University (Full Tuition Fee Scholarship for Naresuan University high-potential graduate-level students fiscal year 2023). N.R. thankfully acknowledges funding from the Royal Thai Government, grant number 3/2563. R.A.B. gratefully acknowledges funding from the Royal Society, grant number RGS\R2\192126.