Development of TPP-HK conjugates as membrane-targeting antibacterial agents against methicillin-resistant Staphylococcus aureus

  • Bioorg Chem. 2025 Aug:163:108758. doi: 10.1016/j.bioorg.2025.108758.
Jizhou Feng  1 ,  Xinyu Li  1 ,  Ruixue Zhang  1 ,  Xinyue Deng  1 ,  Mingxuan Chen  1 ,  Wen Mou  1 ,  Fang Huang  1 ,  Cheng Zou  1 ,  Sheng Zhao  2 ,  Zhi-Peng Wang  3 ,  Chao Huang  4 ,  Yun He  5
Affiliations
  • 1. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
  • 2. College of Bioengineering, Chongqing University, Chongqing 400044, China.
  • 3. Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
  • 4. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China. Electronic address: [email protected].
  • 5. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China; Translational Innovation Center, Shenzhen Bay Laboratory, Shenzhen 518132, China. Electronic address: [email protected].
PMID: 40700930 DOI: 10.1016/j.bioorg.2025.108758
Abstract

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) greatly threatens human health. Here, a series of TPP-HK conjugates with potent Bacterial cytoplasmic membrane-targeting capabilities were developed to combat the escalating threat of MRSA infections. Among them, TH16 showed excellent Antibacterial activity and low frequency resistance. Mechanistic studies revealed that TH16 destroyed the Bacterial cytoplasmic membrane and increased the levels of intracellular ROS, resulting in Bacterial death. Our study demonstrates that TPP-HK conjugates as membrane-targeting agents could be a promising therapeutic strategy against MRSA infections.

Keywords
Honokiol; Membrane-targeting; Methicillin-resistant Staphylococcus aureus; Triphenylphosphonium conjugates.
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