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Biguanide-functionalized peptide mimics effectively combat drug-resistant ESKAPE pathogens and meningitis

Weinan Jiang1, Min Zhou2, Kang Chen2

  • 1Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China.

Nature Communications
|December 9, 2025
PubMed

Insights

New biguanide-based compounds effectively combat drug-resistant ESKAPE pathogens and meningitis. These host defense peptide mimics show potent activity and penetrate the blood-brain barrier, offering a promising therapeutic strategy.

Area of Science:

  • Biochemistry
  • Microbiology
  • Drug Discovery

Background:

  • Meningitis caused by ESKAPE pathogens poses a significant health threat due to antimicrobial resistance and limited blood-brain barrier (BBB) penetration.
  • Conventional treatments are challenged by multidrug-resistant bacteria and the difficulty of delivering therapeutics across the BBB.

Purpose of the Study:

  • To design and evaluate novel synthetic mimics of host defense peptides (HDPs) utilizing biguanide moieties for enhanced antimicrobial activity and BBB penetration.
  • To investigate the efficacy of biguanide-functionalized HDP mimics against ESKAPE pathogens and in various infection models, including meningitis.

Main Methods:

  • Synthesis of a biguanide-functionalized HDP mimic, PBGProOx20.
  • Evaluation of PBGProOx20's interaction with bacterial membrane phospholipids.
  • Assessment of antimicrobial activity against ESKAPE pathogens and determination of resistance induction.
  • Testing of BBB-penetrating properties and therapeutic efficacy in multiple mouse infection models (full-thickness, subcutaneous, kidney, peritonitis, meningitis).

Main Results:

  • Biguanide moieties demonstrated stronger interactions with bacterial membrane phospholipids compared to amine and guanidine via bidentate hydrogen bonds.
  • PBGProOx20 exhibited potent activity against all tested ESKAPE pathogens without inducing antimicrobial resistance.
  • PBGProOx20 showed promising blood-brain barrier penetration and significant therapeutic effects in various infection models, including meningitis.

Conclusions:

  • Biguanide-functionalized HDP mimics represent a promising strategy for developing new therapeutics against drug-resistant ESKAPE pathogens.
  • PBGProOx20 demonstrates potential as an effective treatment for infections, including meningitis, with favorable BBB penetration and no observed resistance induction.

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