Peptide-Mimicking Poly(2-oxazoline)s Possessing Potent Antifungal Activity and BBB Penetrating Property to Treat Invasive Infections and Meningitis

Abstract

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(2oxazoline)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.

Recent Advances in Amphipathic Peptidomimetics as Antimicrobial Agents to Combat Drug Resistance

“…POX-based glycine pseudopeptides showed potent activities against various pathogens. They further design and synthesize guanidinium-functionalized poly(2-oxazoline)s by mimicking cell-penetrating peptides and obtained polymer 28 ( Scheme 8 ) [ 92 ]. Polymer 28 , bearing a methylene spacer arm, displays potent activities against the drug-resistant fungi and biofilm, negligible toxicity, and insusceptibility to antimicrobial resistance.…”

Design, synthesis and bioactivity of a new class of antifungal amino acid‐directed phthalide compounds

“…By introducing green active groups, the properties of compounds can be improved. Jiang et al 18 synthesized a class of antifungal compounds by binding peptide fragments to guanidine, which have potent activities against fungal pathogens and negligible toxicity. Wu et al 19 has developed an amino acid-directed compound design strategy to enhance the activity of the compounds and reduce the risks to the environment.…”

Biophilic Positive Carbon Dot Exerts Antifungal Activity and Augments Corneal Permeation for Fungal Keratitis

“…In recent years, a series of new nanomaterials, , including metal nanoparticles, , borides, nanosized polymers, , and carbon quantum dots, , have been exploited to kill fungi. Among them, carbon quantum dots (CQDs) are zero-dimensional carbon nanostructured materials with diameters of less than 10 nm. , The ultrasmall size provides a natural advantage to pass through the corneal barrier.…”