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

ABSTRACT

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.