Discovery and Characterization of a Disulfide-Locked <i>C</i>₂‑Symmetric Defensin Peptide

We report the discovery of HD5-CD, an unprecedented <i>C</i>₂-symmetric β-barrel-like covalent dimer of the cysteine-rich host-defense peptide human defensin 5 (HD5). Dimerization results from intermonomer disulfide exchange between the canonical α-defensin Cys^II–Cys^IV (Cys⁵–Cys²⁰) bonds located at the hydrophobic interface. This disulfide-locked dimeric assembly provides a new element of structural diversity for cysteine-rich peptides as well as increased protease resistance, broad-spectrum antimicrobial activity, and enhanced potency against the opportunistic human pathogen Acinetobacter baumannii