Cationizing Lugdunin through Trp3 Hydrophobic Fine-Tuning and Cationic Side Chain Engineering.

Lugdunin, a nonpolar cyclic peptide antibiotic, features a unique structural core, making it particularly rare and promising in the landscape of antibiotic discovery. However, its inherent structural limitations have severely hindered its further optimization and clinical translation. To break through these limitations, we employed a combination of Tryptophan3 (Trp3) hydrophobic fine-tuning and cationic engineering strategies to cationize Lugdunin and synthesized a series of cationic Lugdunin derivatives. Among them, W17 demonstrated remarkable antibacterial activity against pathogens like Methicillin-resistant Staphylococcus aureus (MRSA), rapid bactericidal action and a low propensity to induce resistance. This stems from a synergistic "membrane disruption-ROS (Reactive Oxygen Species) cascade" dual mechanism acquired via cationization, differing fundamentally from Lugdunin. W17 demonstrated excellent stability and biocompatibility. Crucially, it showed significant therapeutic efficacy in MRSA pneumonia mouse model, strongly supporting its clinical potential. Collectively, Lugdunin cationization markedly enhance its clinical application prospects, offering new antibiotic candidates for combating resistant infections.

• Publication year

  2026

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2026-01-14

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.5c02219PMID 41532997
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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