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

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.