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

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.