Design and synthesis of novel anti-multidrug-resistant staphylococcus aureus derivatives of glycyrrhetinic acid by blocking arginine biosynthesis, metabolic and H2S biogenesis

Bioorg Chem. 2023 Feb:131:106337. doi: 10.1016/j.bioorg.2022.106337. Epub 2022 Dec 30.

Abstract

With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 μM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 μM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 μM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.

Keywords: Amino acids; Glycyrrhetinic acid derivatives; Ligustrazine; Multi-resistant Staphylococcus aureus; RNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents* / pharmacology
  • Arginine* / biosynthesis
  • Drug Design*
  • Escherichia coli / drug effects
  • Glycyrrhetinic Acid* / analogs & derivatives
  • Glycyrrhetinic Acid* / pharmacology
  • Humans
  • Hydrogen Sulfide / metabolism
  • Methicillin-Resistant Staphylococcus aureus* / drug effects
  • Microbial Sensitivity Tests
  • Staphylococcal Infections*
  • Staphylococcus aureus / drug effects

Substances

  • Anti-Bacterial Agents
  • Arginine
  • Glycyrrhetinic Acid
  • Hydrogen Sulfide