Phylloseptin

Phylloseptins are unstructured in aqueous solution but rapidly fold into amphipathic alpha-helices upon contact with bacterial membranes or membrane-mimetic environments. The C-terminal amidation increases net cationic charge and enhances binding to negatively charged bacterial phospholipids. The helical structure creates a hydrophobic face that inserts into the hydrophobic core of the membrane, leading to disruption through a carpet or detergent-like mechanism.

Some phylloseptin analogs (PS-H4 and related) have been modified to function as cell-penetrating peptides capable of delivering cargo into mammalian cells. The short helical structure with positively charged residues at one face facilitates endosomal escape after endocytosis. This dual antimicrobial/cell-penetrating function distinguishes phylloseptins as versatile scaffolds for both antibiotic and drug delivery applications.

Phylloseptin-1 and PS-L1 show potent activity against Candida albicans and Candida tropicalis at MIC values of 2-8 ug/mL. Antifungal activity operates through membrane disruption distinct from clinical azole targets, suggesting utility against azole-resistant Candida strains. Biofilm studies indicate partial activity against mature Candida biofilms, which are notoriously resistant to conventional antifungals.

Several phylloseptin family members show preferential cytotoxicity against HeLa, MCF-7, and PC-3 cancer cell lines with selectivity indexes (SI = HC50/IC50) above 10. SAR optimization studies have been performed to improve selectivity while maintaining potency, identifying hydrophobicity and helical stability as key parameters for cancer cell vs. normal cell discrimination.