The emergence of multidrug-resistant (MDR) Gram-negative pathogens has become an urgent global medical challenge. The old polymyxin antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetic (poor exposure in the lungs) and efficacy (poor activity against pulmonary infections) issues that have limited their therapeutic usefulness. Through structural modification of multiple non-conserved positions in the polymyxin scaffold, we were able to successfully disconnect the therapeutic efficacy from the toxicity for this class of peptides. This resulted in the development of the clinical candidate F365 (QPX9003), a next-generation synthetic polymyxin with significantly improved safety and efficacy against lung infections caused by the top-priority pathogens, MDR Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.