Dual-targeting amphiphilic lipopeptides combat multidrug-resistant Gram-positive pathogens by inhibiting type I signal peptidase and disrupting bacterial membrane

  • Eur J Med Chem. 2026 Jan 5:301:118244. doi: 10.1016/j.ejmech.2025.118244.
Xiaolin Lu  1 ,  Xianghan Xu  2 ,  Xin Kang  2 ,  Xin Gong  3 ,  Junli Feng  3 ,  Mengkang Gao  3 ,  Hao Yin  3 ,  Zhi Wang  3 ,  Xingyu Xia  3 ,  Jiaqi Zhao  2 ,  Liping Wang  4 ,  Dayong Zhang  5 ,  Jinhu Huang  6 ,  Menghan Zhang  7
Affiliations
  • 1. School of Science, China Pharmaceutical University, Nanjing, 211198, PR China; School of Pharmacy, Shanxi Medical University, Taiyuan, 030001, PR China.
  • 2. MOE Joint International Research Laboratory of Animal Health and Food Safety, Risk Assessment Center of Veterinary Drug Residue and Antimicrobial Resistance, Center for Veterinary Drug Research and Evaluation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China; Sanya Institute of Nanjing Agricultural University, Nanjing Agricultural University, Sanya, 572025, PR China.
  • 3. School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 4. MOE Joint International Research Laboratory of Animal Health and Food Safety, Risk Assessment Center of Veterinary Drug Residue and Antimicrobial Resistance, Center for Veterinary Drug Research and Evaluation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
  • 5. School of Science, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: [email protected].
  • 6. MOE Joint International Research Laboratory of Animal Health and Food Safety, Risk Assessment Center of Veterinary Drug Residue and Antimicrobial Resistance, Center for Veterinary Drug Research and Evaluation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China; Sanya Institute of Nanjing Agricultural University, Nanjing Agricultural University, Sanya, 572025, PR China. Electronic address: [email protected].
  • 7. School of Science, China Pharmaceutical University, Nanjing, 211198, PR China; School of Basic Medicine and Clinical Pharmacy, Institute of Translational Medicine, China Pharmaceutical University, Nanjing, 211112, PR China. Electronic address: [email protected].
PMID: 41067052 DOI: 10.1016/j.ejmech.2025.118244
Abstract

Antimicrobial resistance poses a significant threat to global health, particularly with multidrug-resistant (MDR) Gram-positive pathogens evading last-line treatments. We herein designed and synthesized novel amphiphilic Lipopeptide derivatives to exert dual Antibacterial mechanisms: SPase I inhibition and Bacterial membrane disruption. Among these, compound A09 demonstrated potent in vitro activity against a series of MDR Gram-positive pathogens. Biochemical characterization revealed potent inhibition of Escherichia coli SPase I (LepB) with an IC50 of 4.475 μM and a Kd of 16.3 ± 11.4 μM. Mechanistic studies confirmed A09's membrane disruption and significant biofilm eradication capability. Critically, A09 exhibited substantial efficacy in vivo in a murine model of methicillin-resistant Staphylococcus aureus (MRSA) skin Infection. Furthermore, A09 displayed low hemolytic and cytotoxic effects, indicating a favorable safety profile. These results established A09 as a promising dual-mechanism anti-infective agent for treating drug-resistant Gram-positive infections.

Keywords
Amphiphilic lipopeptides; Bacterial membrane; Multidrug resistance; Novel antibiotics; SPase I.
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