An α-Lipoic acid derivative, and anti-ROS agent, prevents the acquisition of multi-drug resistance in clinical isolates of Pseudomonas aeruginosa

J Infect Chemother. 2019 Jan;25(1):28-33. doi: 10.1016/j.jiac.2018.10.003. Epub 2018 Nov 3.

Abstract

Pseudomonas aeruginosa is one of the most common causes of nosocomial infections, and its multi-drug resistance has been a serious problem worldwide. The aim of this study was to evaluate whether exposure to piperacillin and reactive oxygen species (ROS) could lead to multi-drug resistance for clinical isolates of P. aeruginosa. The inhibition of this acquired resistance by the anti-ROS agent was also examined. In vitro inducement of multi-drug resistance was performed against 20 clinical isolates. These strains were incubated for 24 h and transferred 5 times after being exposed to 1 mM H2O2 (ROS) in addition to a sub-MIC of piperacillin by the agar dilution method. Each MIC of piperacillin and levofloxacin was determined. As the mechanism of levofloxacin resistance, mutation of QRDR was investigated. The expression level of genes encoding efflux pumps; mexA, mexY, mexC, and D2 porin; oprD were determined by real-time PCR. Multi-resistance to both piperacillin and levofloxacin was induced with 4 of 20 strains (20%). No amino acid change was confirmed in QRDR. These strains showed overexpression of mexA, mexY, mexC, and another one showed decrease of oprD expression. Resistance development in 4 strains was inhibited by the same method including the anti-ROS agent, sodium zinc histidine dithiooctanamide (DHL-His-Zn). In conclusion, stimulation by ROS promoted acquisition of multi-drug resistance in 20% of isolates of P. aeruginosa, and DHL-His-Zn completely inhibited this acquisition of resistance. Therefore, this anti-ROS agent may be useful to assist antimicrobial chemotherapy by preventing multi-drug resistance.

Keywords: Efflux pump; Multi-drug resistance; Pseudomonas aeruginosa; Reactive oxygen species; Sodium zinc histidine dithiooctamide.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Antioxidants / pharmacology
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / metabolism
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Resistance, Multiple, Bacterial / genetics
  • Histidine / analogs & derivatives*
  • Histidine / pharmacology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Levofloxacin / pharmacology
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Piperacillin / pharmacology
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / isolation & purification
  • Reactive Oxygen Species / metabolism
  • Thioctic Acid / analogs & derivatives*
  • Thioctic Acid / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Antioxidants
  • Bacterial Outer Membrane Proteins
  • Membrane Transport Proteins
  • MexA protein, Pseudomonas aeruginosa
  • MexC protein, Pseudomonas aeruginosa
  • Reactive Oxygen Species
  • zinc histidine dithiooctanamide
  • Histidine
  • Levofloxacin
  • Thioctic Acid
  • Hydrogen Peroxide
  • Piperacillin