Membrane-Targeting Amphiphilic Honokiol Derivatives Containing an Oxazole Moiety as Potential Antibacterials against Methicillin-Resistant Staphylococcus aureus

Infections with methicillin-resistant Staphylococcus
aureus (MRSA) are becoming increasingly serious, making
the development of novel antimicrobials urgent. Here, we synthesized
some amphiphilic honokiol derivatives bearing an oxazole moiety and
investigated their antibacterial and hemolytic activities. Bioactivity
evaluation showed that E17 possessed significant in vitro antibacterial activity against S.
aureus and MRSA, along with low hemolytic activity.
Moreover, E17 exhibited rapid bactericidal properties
and was not susceptible to resistance. Mechanistic studies indicated
that E17 interacts with phosphatidylglycerol and cardiolipin
of bacterial cell membranes, leading to changes in cell membrane permeability
and polarization, increased intracellular ROS, and leakage of DNA
and proteins, thus accelerating bacterial death. Transcriptome analysis
further demonstrated that E17 has membrane-targeting
effects, affecting the expression of genes related to cell membranes
and ABC transporter proteins. Notably, in vivo activity
showed that E17 has prominent anti-MRSA efficacy, comparable
to vancomycin, and is expected to be a new anti-MRSA drug candidate.