Peptide-Mimicking Poly(2-oxazoline)s Possessing Potent Antifungal Activity and BBB Penetrating Property to Treat Invasive Infections and Meningitis.
Weinan JiangMin ZhouSheng ChenJiayang XieMinzhang ChenHaodong ZhangYueming WuXin ChenRunhui LiuPublished in: Journal of the American Chemical Society (2023)
Invasive fungal infections, including meningitis, cause a high mortality rate due to few available antifungal drugs and frequently associated side effects and quick emergence of drug-resistant fungi. The restrictive permeability of the blood-brain barrier (BBB) further limits the efficacy of antifungal agents substantially in treating meningitis. Hereby, we design and synthesize guanidinium-functionalized poly(2-oxazoline)s by mimicking cell-penetrating peptides. The optimal polymer, PGMeOx 10 bearing a methylene spacer arm, displays potent activities against the drug-resistant fungi and biofilm, negligible toxicity, and insusceptibility to antimicrobial resistance. Moreover, PGMeOx 10 can break BBB retractions to exert promising antifungal functions in the brain. PGMeOx 10 demonstrates potent in vivo antifungal therapeutic efficacy in mouse models including skin infection, systemic infections, and meningitis. PGMeOx 10 effectively rescues infected mice and reduces fungal burden and inflammation in the brain. These results and the excellent biosafety of poly(2-oxazoline)s indicate the effectiveness and potential of our strategy to design promising antifungal agents in treating systemic infections and meningitis.
Keyphrases
- drug resistant
- candida albicans
- multidrug resistant
- acinetobacter baumannii
- cerebrospinal fluid
- antimicrobial resistance
- blood brain barrier
- biofilm formation
- mouse model
- oxidative stress
- randomized controlled trial
- pseudomonas aeruginosa
- resting state
- systematic review
- anti inflammatory
- staphylococcus aureus
- stem cells
- type diabetes
- metabolic syndrome
- mass spectrometry
- cerebral ischemia
- cardiovascular events
- risk assessment
- brain injury
- cystic fibrosis
- human health
- cardiovascular disease
- tandem mass spectrometry