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Published on: September 8, 2021
Membrane-Targeting Amphiphilic Honokiol Derivatives Containing an Oxazole Moiety as Potential Antibacterials against
Ruige Yang1,2, Liping Cui2, Shengnan Xu1
1Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan Province 421001, China.
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.
Insights
A new honokiol derivative, E17, shows potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). This novel antimicrobial agent targets bacterial membranes and demonstrates significant efficacy in vivo, offering a promising candidate for combating MRSA infections.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Pharmacology
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a significant global health threat.
- Urgent need for novel antimicrobial agents to overcome existing resistance mechanisms.
Purpose of the Study:
- To synthesize and evaluate novel amphiphilic honokiol derivatives with antibacterial activity.
- To investigate the antibacterial spectrum, resistance potential, and mechanism of action of promising candidates.
- To assess the in vivo efficacy of the lead compound against MRSA.
Main Methods:
- Synthesis of amphiphilic honokiol derivatives containing an oxazole moiety.
- In vitro assessment of antibacterial activity against Staphylococcus aureus and MRSA.
- Hemolytic activity assays.
- Bactericidal kinetics and resistance development studies.
- Mechanistic investigations including membrane interaction, ROS generation, and DNA/protein leakage.
- Transcriptome analysis.
- In vivo efficacy studies in a murine model.
Main Results:
- Compound E17 demonstrated significant in vitro antibacterial activity against S. aureus and MRSA with low hemolytic activity.
- E17 exhibited rapid bactericidal effects and was not susceptible to resistance development.
- Mechanistic studies revealed E17 targets bacterial cell membranes, altering permeability, increasing ROS, and causing leakage of cellular contents.
- Transcriptome analysis confirmed membrane-targeting effects and modulation of ABC transporter gene expression.
- In vivo studies showed E17 possessed anti-MRSA efficacy comparable to vancomycin.
Conclusions:
- The honokiol derivative E17 is a potent anti-MRSA agent with a novel membrane-targeting mechanism.
- E17 displays rapid bactericidal activity, low resistance potential, and favorable in vivo efficacy.
- E17 represents a promising drug candidate for the development of new therapies against MRSA infections.
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