Single Amino Acid Modulates Antimicrobial Peptide Cooperativity between LL-37 and HNP1

Antimicrobial peptides (AMPs) are promising agents against infections caused by multidrug-resistant bacteria. Notably, the human AMPs LL-37 and α-defensin (HNP1) exhibit a cooperative effect, synergistically killing bacteria while reducing host cytotoxicity. However, the structural-function relationship of this phenomenon remains unclear. Here, we report that the previously observed neutralization of LL-37 toxicity against POPC membranes by HNP1 is not unique to this pair but can be extended to other members of the defensin family including HNP3, HNP4, and hBD1. This cooperative effect, however, was absent in HNP2. By comparing amino acid sequences, we identified that the N-terminus of the defensins modulates the cooperative effect between LL-37 and the defensins.