Discovery of di-amino acid antimicrobial peptide mimetics with heteroatom-incorporated linkers for potent antibacterial activity and low hemolytic toxicity

  • Eur J Med Chem. 2026 May 27:316:119013. doi: 10.1016/j.ejmech.2026.119013.
Hongtao Kong  1 ,  Saiya Yang  1 ,  Yarui Fu  1 ,  Yuyang Ma  1 ,  Mingzhe Zhang  1 ,  Yonghui Shen  1 ,  Zhi-Hao Li  2 ,  En Zhang  3 ,  Yong-Yao Li  4
Affiliations
  • 1. School of Pharmaceutical Sciences, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, China.
  • 2. State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
  • 3. School of Pharmaceutical Sciences, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
PMID: 42208370 DOI: 10.1016/j.ejmech.2026.119013
Abstract

The rise of multidrug-resistant Bacterial infections severely endangers human health. Herein, we prepared two classes of di-amino acid antimicrobial peptide mimetics bearing either simple alkyl chains or heteroatom-incorporated alkyl chains as linkers. The mimetics bearing simple alkyl chains as linkers all exhibited high hemolytic toxicity, whereas the compounds with heteroatom-containing alkyl chains as linkers displayed both potent Antibacterial activity and low hemolytic toxicity. Among them, 7d exhibited potent Antibacterial effects against S. aureus and MRSA (MIC = 0.5-1 μg/mL), along with low hemolytic toxicity. Moreover, 7d was characterized by rapid bactericidal kinetics and a low potential for resistance emergence. Furthermore, 7d both prevented S. aureus biofilm formation and disrupted established biofilms. Mechanistic and transcriptomic analyses indicated that 7d kills bacteria by disrupting the cell membrane, causing ROS accumulation and metabolic disturbances. Importantly, 7d showed strong in vivo Antibacterial activity in a mouse subcutaneous Infection model. Collectively, these results suggest that 7d is a promising lead compound for treating Bacterial infections.

Keywords
Amino acids; Antimicrobial peptide mimics; Biofilm; S. aureus.
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