In vitro activity and In vivo efficacy of Isoliquiritigenin against Staphylococcus xylosus ATCC 700404 by IGPD target

PLoS One. 2019 Dec 20;14(12):e0226260. doi: 10.1371/journal.pone.0226260. eCollection 2019.

Abstract

Staphylococcus xylosus (S. xylosus) is a type of coagulase-negative Staphylococcus, which was previously considered as non-pathogenic. However, recent studies have linked it with cases of mastitis in cows. Isoliquiritigenin (ISL) is a bioactive compound with pharmacological functions including antibacterial activity. In this study, we evaluated the effect of ISL on S. xylosus in vitro and in vivo. The MIC of ISL against S. xylosus was 80 μg/mL. It was observed that sub-MICs of ISL (1/2MIC, 1/4MIC, 1/8MIC) significantly inhibited the formation of S. xylosus biofilm in vitro. Previous studies have observed that inhibiting imidazole glycerol phosphate dehydratase (IGPD) concomitantly inhibited biofilm formation in S. xylosus. So, we designed experiments to target the formation of IGPD or inhibits its activities in S. xylosus ATCC 700404. The results indicated that the activity of IGPD and its histidine content decreased significantly under 1/2 MIC (40 μg/mL) ISL, and the expression of IGPD gene (hisB) and IGPD protein was significantly down-regulated. Furthermore, Bio-layer interferometry experiments showed that ISL directly interacted with IGPD protein (with strong affinity; KD = 234 μM). In addition, molecular docking was used to predict the binding mode of ISL and IGPD. In vivo tests revealed that, ISL significantly reduced TNF-α and IL-6 levels, mitigated the destruction of the mammary glands and reversed the production of inflammatory cells in mice. The results of the study suggest that, ISL may inhibit S. xylosus growth by acting on IGPD, which can be used as a target protein to treat infections caused by S. xylosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Biofilms / drug effects
  • Chalcones / administration & dosage*
  • Chalcones / chemistry
  • Chalcones / pharmacology
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Bacterial / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hydro-Lyases / antagonists & inhibitors*
  • Hydro-Lyases / chemistry
  • Mastitis / drug therapy*
  • Mice
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Docking Simulation
  • Staphylococcal Infections / drug therapy*
  • Staphylococcus / drug effects*
  • Staphylococcus / enzymology
  • Staphylococcus / growth & development

Substances

  • Bacterial Proteins
  • Chalcones
  • isoliquiritigenin
  • Hydro-Lyases
  • imidazoleglycerolphosphate dehydratase

Supplementary concepts

  • Staphylococcus xylosus

Grants and funding

This work was supported by the National Key Research and Development Program of China (2018YFD0500300), Ministry of Agriculture Pig Industry System (CARS-35) and National Nature Science Foundation of China (Grant No. 31772787). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.