Identification of Rutaecarpine-Pyridinium Quaternary Ammonium Conjugates Exhibiting Dual Mechanisms of Membrane-Targeting and DNA Topo I Inhibition as Potent Antimicrobials against Methicillin-Resistant Staphylococcus aureus

The
structural diversity of natural products provides a major source
for discovering antimicrobials with novel structures or mechanisms
to overcome microbial resistance. Herein, we prepared a series of
rutaecarpine-pyridinium quaternary ammonium conjugates by using rutaecarpine
as the lead compound. Bioactivity evaluation demonstrated that 5dl exhibits outstanding antibacterial activity against S. aureus ATCC 29213 and clinical MRSA isolates,
with MIC values ranging from 0.5 to 2 μg/mL, comparable to vancomycin.
Low hemolysis, low resistance frequency, low cytotoxicity, rapid bactericidal
properties, and good plasma stability indicate the further application
potential of 5dl. Notably, 5dl exhibited
better therapeutic efficacy than vancomycin in two mouse models of
MRSA infection. Mechanistic studies revealed that 5dl not only targetingly disrupts the MRSA cell membranes but also inhibits
Topo I activity, thereby interfering with DNA replication and transcription
processes, ultimately leading to MRSA cell death. These findings demonstrate
that 5dl could serve as a promising candidate for combating
MRSA infections.