An Effective Strategy to Develop Potent and Selective Antifungal Agents from Cell Penetrating Peptides in Tackling Drug-Resistant Invasive Fungal Infections

The high mortality rate of invasive fungal infections and quick emergence of drug-resistant fungal pathogens urgently call for potent antifungal agents. Inspired by the cell penetrating peptide (CPP) octaarginine (R8), we elongated to 28 residues poly(d,l-homoarginine) to obtain potent toxicity against both fungi and mammalian cells. Further incorporation of glutamic acid residues shields positive charge density and introduces partial zwitterions in the obtained optimal peptide polymer that displays potent antifungal activity against drug-resistant fungi superior to antifungal drugs, excellent stability upon heating and UV exposure, negligible in vitro and in vivo toxicity, and strong therapeutic effects in treating invasive fungal infections. Moreover, the peptide polymer is insusceptible to antifungal resistance owing to the unique CPP-related antifungal mechanism of fungal membrane penetration followed by disruption of organelles within fungal cells. All these merits imply the effectiveness of our strategy to develop promising antifungal agents.