Discovery of Novel Coumarin Pleuromutilin Derivatives as Potent Anti-MRSA Agents

J Med Chem. 2024 Dec 12;67(23):21030-21048. doi: 10.1021/acs.jmedchem.4c01678. Epub 2024 Nov 27.

Abstract

Treating methicillin-resistant Staphylococcus aureus (MRSA) infection remains one of the most difficult challenges in clinical practice, primarily due to the resistance of MRSA to multiple antibiotics. Therefore, there is an urgent need to develop novel antibiotics with high efficacy and low cross-resistance rates. In this study, a series of novel pleuromutilin derivatives with coumarin structures were synthesized and subsequently assessed for their biological activities. Most of these derivatives showed potent antimicrobial activity against drug-resistant Gram-positive bacterial strains. Compound 14b displayed particularly rapid bactericidal effects, slow resistance development, and low cytotoxicity. Moreover, it decreased bacterial loads in the lung, liver, kidney, spleen, and heart and exhibited better antibacterial efficacy (ED50 = 11.16 mg/kg) than tiamulin (ED50 = 28.93 mg/kg) in a mouse model of systemic MRSA infection. Both in vitro and in vivo analyses suggest that compound 14b is a promising agent for the treatment of MRSA infections.

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / chemical synthesis
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Coumarins* / chemical synthesis
  • Coumarins* / chemistry
  • Coumarins* / pharmacology
  • Diterpenes* / chemical synthesis
  • Diterpenes* / chemistry
  • Diterpenes* / pharmacology
  • Drug Discovery
  • Humans
  • Methicillin-Resistant Staphylococcus aureus* / drug effects
  • Mice
  • Microbial Sensitivity Tests*
  • Pleuromutilins*
  • Polycyclic Compounds* / pharmacology
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / microbiology
  • Structure-Activity Relationship

Substances

  • Pleuromutilins
  • Polycyclic Compounds
  • Anti-Bacterial Agents
  • Diterpenes
  • Coumarins