2. Academic Validation
  3. Structural optimization of natural product honokiol to discover novel membrane-targeting antibacterial agents against Gram-positive bacteria

Structural optimization of natural product honokiol to discover novel membrane-targeting antibacterial agents against Gram-positive bacteria

  • Eur J Med Chem. 2026 Apr 5:307:118674. doi: 10.1016/j.ejmech.2026.118674.
Ninan Dai 1,  Yiyu Wang 1,  Yong Yang 1,  Yuting Zhang 1,  Huan Ge 2,  Farhad Ghazali 3,  Bao Fu 4,  Yinhu Wang 5,  Song Qin 6
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China.
  • 2 School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, 252059, China.
  • 3 School of Medicine, University of California, San Francisco, CA, 94143, USA.
  • 4 Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China. Electronic address: fubao0607@126.com.
  • 5 School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, 252059, China. Electronic address: wangyinhuabc@126.com.
  • 6 Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China. Electronic address: qinsong@zmu.edu.cn.
PMID: 41689937 DOI: 10.1016/j.ejmech.2026.118674
Abstract

The global increase in infections caused by multidrug-resistant bacteria, coupled with a dwindling Antibiotic pipeline, underscores an urgent need for new therapeutic agents. Inspired by the design principles of cationic antimicrobial peptides, we developed a new class of honokiol-based amphiphiles. From this series, compound 20C emerged as a promising lead, demonstrating potent in vitro activity against Gram-positive bacteria (MICs = 0.5-2 μg/mL). It exhibited a favorable safety profile characterized by low hemolytic (HC50 = 771.8 μg/mL) and cytotoxic activity (CC50 = 28.03 μg/mL), along with good plasma stability. 20C also displayed rapid bactericidal kinetics, a low resistance frequency, and efficacy in inhibiting biofilm formation and disrupting mature biofilms. A detailed mechanistic investigation established that 20C exerted its effect by dissipation of membrane potential, increasing permeability, thereby disrupting membrane integrity. This primary membrane damage triggered secondary lethal events, including ROS accumulation and leakage of proteins and DNA. Notably, 20C displayed superior efficacy compared to vancomycin in an in vivo Infection model. These findings established 20C as a promising candidate and underscore the potential of this amphiphilic design strategy in Antibiotic discovery.

Keywords

Antimicrobial peptides; Bacterial infections; Honokiol derivatives; Membrane damage.

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