Peptide antibiotics are a promising source of molecular diversity but often suffer from cytotoxicity, limiting clinical development. This study reports the structure-guided optimization of the amphipathic peptide arenicin-3, resulting in AA139. AA139 exhibits broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant Gram-negative bacteria, including clinical isolates resistant to last-resort antibiotics. It shows efficacy in mouse models of infection, with reduced cytotoxicity and hemolysis compared to the progenitor. The no observable adverse effect level (NOAEL) in mice is ~10-fold higher than the effective dose in infection models.

Alysha G. Elliott, Johnny X. Huang, Søren Neve, Johannes Zuegg, Ingrid A. Edwards, Amy K. Cain, Christine J. Boinett, Lars Barquist, Carina Vingsbo Lundberg, Jason Steen, Mark S. Butler, Mehdi Mobli, Kaela M. Porter, Mark A. T. Blaskovich, Sergio Lociuro, Magnus Strandh, Matthew A. Cooper