ABSTRACT The goal of this project is to develop a broad-spectrum dry powder inhalation teixobactin-lipopeptide hybrid aimed at preventing and treating lung infections caused by bacterial `superbugs'. The successful use of any antibiotic is compromised by the potential development of resistance to that compound from the time it is first used. The world is facing an enormous and growing threat from the emergence of pan-drug resistant (PDR) bacteria that are resistant to all available antibiotics. New antibiotics with 1) novel mechanisms of action and 2) against which bacteria cannot easily develop resistance are urgently needed to treat lung infections caused by the PDR Gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae and Gram-positive strains of methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. Teixobactin is a recently discovered new antibiotic that possesses a novel mechanism of action (MOA), albeit, a narrow spectrum of activity against Gram-positive bacteria. The most notable property of teixobactin is that it is the first and only antibiotic that bacteria cannot easily develop resistance against. We have developed novel teixobactin-lipopeptide hybrids that are superior to native teixobactin as they retain this key anti-resistance property and in addition have a broader-spectrum, with potent activity against PDR Gram-negatives, as well as PDR Gram-positives. Our preliminary data show that our teixobactin-lipopeptide hybrids delivered as a dry powder inhalation have significantly improved efficacy for the treatment of lung infections by virtue of their unique MOA, no detectable resistance, high local exposure in the lungs with low systemic exposure and low toxicity. Importantly, the hybrids displayed superior in vivo efficacy compared to treatment with the combination of the individual compounds or each compound per se. This is a significant development in the field as the teixobactin-lipopeptide hybrid represents the first-in class broad-spectrum `resistance-proof' dry powder inhalation antibiotic for the treatment of PDR bacterial lung infections. Our internationally recognized track records in antibiotic discovery, pharmacology, anti-infective dry powder formulation, pharmacokinetics/pharmacodynamics and state-of-the-art facilities for antimicrobial development provide extremely strong support for this project. The proposal will employ a purpose designed funneling approach to identify a lead candidate (plus one back-up) that is active against PDR Gram-negative strains of P. aeruginosa, A. baumannii and K. pneumoniae and Gram-positive strains of MRSA and S. pneumoniae for preclinical development and IND-enabling studies.