Antimicrobial resistance has become a major global health challenge. The Gram-negative ‘superbugs’ Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae can develop resistant to all currently available antibiotics. They have been identified as the top-priority pathogens by the World Health Organization (WHO), as no novel antibiotics will be available in the near future. Polymyxin B and colistin have been increasingly used as a last-line therapy against these problematic Gram-negative pathogens. However, their effective use in patients has been severely hampered by dose-limiting nephrotoxicity, acute neurotoxicity, poor lung exposure, binding to lung surfactant, and poor activity against pneumonia. It is very difficult to structurally disconnect the efficacy from toxicity for the polymyxins due to the interplay of their structure-activity relationship (SAR), structure-toxicity relationship (STR) and structure-pharmacokinetics relationship (SPR). This is evident by the fact that no new polymyxin drugs have been approved since the 1960s. Here, I will provide an overview of my team’s discovery of a novel lipopeptide antibiotic QPX9003, which was initiated with a new SAR model and underpinned by 20-year pharmacology research. We rationally navigated the narrow chemical space of polymyxins and successfully disconnected the efficacy from toxicities by balancing the complex interrelationships between the SAR/STR/SPR axis. This eventuated in the development of our clinical candidate QPX9003 which displayed superior safety in rodents and monkeys, and superb in vivo efficacy against pneumonia. Funded by our industry partner Qpex Biopharma (US) and the US Biomedical Advanced Research and Development Authority (BARDA), Phase 1 clinical trials of QPX9003 have successfully completed. QPX9003 showed no toxicity at the highest dose (400 mg) administered in the single ascending dose study in healthy human subjects. Our drug discovery program highlights how international academic-industry collaborations can be successfully executed to deliver outcomes with the potential for providing significant real-world value for human health.