Biguanide-functionalized peptide mimics effectively combat drug-resistant ESKAPE pathogens and meningitis
ESKAPE pathogens-induced meningitis seriously threatens human health due to antimicrobial resistance and low permeability of blood-brain barrier (BBB). It's a promising strategy to combat drug-resistant pathogens using synthetic mimics of host defense peptide (HDP) bearing positive charges that are mainly provided by amine or guanidine. Here, we report that biguanide serves as a type of positively charged moiety to design HDP mimics. Biguanide exerts a stronger interaction with bacterial membrane phospholipids via bidentate hydrogen bonds than do amine and guanidine. The biguanide-functionalized HDP mimic, PBGProOx<sub>20</sub>, targets bacterial membrane phospholipids to show potent activity against all ESKAPE pathogens and does not induce antimicrobial resistance. PBGProOx<sub>20</sub> exhibits promising BBB-penetrating property and displays potent therapeutic effects in female mice full-thickness infection model, sub-cutaneous infection model, kidney infection model, peritonitis model, and meningitis model. This study provides a promising strategy for designing HDP mimics to combat ESKAPE pathogens and meningitis.
Authors
- Longqiang Liu (ORCID: https://orcid.org/0000-0002-9849-3821)
- Zihao Cong (ORCID: https://orcid.org/0000-0003-3462-7373)
- Ximian Xiao (ORCID: https://orcid.org/0000-0002-7096-8784)
- Minzhang Chen (ORCID: https://orcid.org/0000-0002-5377-7732)
- Runhui Liu (ORCID: https://orcid.org/0000-0002-7699-086X)
- Weinan Jiang (ORCID: https://orcid.org/0000-0001-5393-5713)
- Min Zhou (ORCID: https://orcid.org/0000-0002-0444-0324)
- Yueming Wu (ORCID: https://orcid.org/0000-0001-7668-7409)
- Jiayang Xie (ORCID: https://orcid.org/0000-0002-3399-0894)
- Sheng Chen (ORCID: https://orcid.org/0000-0001-9090-3905)
- Kang Chen (ORCID: https://orcid.org/0000-0002-9494-2685)
- Haodong Zhang (ORCID: https://orcid.org/0000-0002-1186-8732)
- Jia Shi (ORCID: https://orcid.org/0009-0001-3995-6697)
Institutions
- East China University of Science and Technology (CN)
- Chinese Academy of Sciences (CN)
- Suzhou Institute of Biomedical Engineering and Technology (CN)
- Shanghai Institute of Pharmaceutical Industry (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1038/s41467-025-67044-5
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- China Postdoctoral Science Foundation
- East China University of Science and Technology
- Shanghai Municipal Education Commission
- Chinese Academy of Medical Sciences
- State Key Laboratory of Polymer Physics and Chemistry
- Changchun Institute of Applied Chemistry
- National Key Research and Development Program of China