Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

Molecules. 2022 Jan 29;27(3):931. doi: 10.3390/molecules27030931.

Abstract

A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10-8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10-8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL).

Keywords: 50S ribosome; MRSA; SPR; antibacterial activity; pleuromutilin.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Diterpenes / therapeutic use*
  • Drug Discovery*
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / isolation & purification*
  • Mice
  • Pleuromutilins
  • Polycyclic Compounds / therapeutic use*
  • Staphylococcal Infections / drug therapy*
  • Surface Plasmon Resonance

Substances

  • Anti-Bacterial Agents
  • Diterpenes
  • Polycyclic Compounds