Abstract

Significance We developed antimicrobial polypeptides (AMPs) with unprecedented radial amphiphilicity. Unlike typical AMPs characterized by facial amphiphilicity or biomimetic antimicrobial polymers with randomly distributed charged and hydrophobic groups, this class of AMPs is made up of homo-polypeptides that feature a radially amphiphilic (RA) structure and adopt a stable α-helical conformation with a hydrophobic helical core and a charged exterior shell, which is formed by flexible hydrophobic side chains with terminal charge group. The RA polypeptides appear to offer several advantages over conventional AMPs with regard to stability against proteases and simplicity of design. They also exhibit high antibacterial activity against both gram-negative and gram-positive bacteria and low hemolytic activity. This design may become a general platform for developing AMPs to treat drug-resistant bacteria.