@article{f12b3757be7d4f7e9493b94f90867a65,
title = "A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens",
abstract = "The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide 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 issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.",
author = "Roberts, {Kade D.} and Yan Zhu and Azad, {Mohammad A.K.} and Han, {Mei Ling} and Jiping Wang and Lynn Wang and Yu, {Heidi H.} and Horne, {Andrew S.} and Pinson, {Jo Anne} and David Rudd and Voelcker, {Nicolas H.} and Patil, {Nitin A.} and Jinxin Zhao and Xukai Jiang and Jing Lu and Ke Chen and Olga Lomovskaya and Hecker, {Scott J.} and Thompson, {Philip E.} and Nation, {Roger L.} and Dudley, {Michael N.} and Griffith, {David C.} and Tony Velkov and Jian Li",
note = "Funding Information: This work was supported by research grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI098771 and AI132154). N.A.P. is an Australia National Health and Medical Research Council (NHMRC) Peter Doherty Fellow. J.Li. is an Australia NHMRC Principal Research Fellow. The authors thank Ms. Jesmin Akter, Hasini Walpola, Jie Lu, and Mr. Yang Hu for their technical support in the pharmacological experiments, the Phenomics Network-Histopathology and Organ Pathology (University of Melbourne, Parkville, VIC, Australia) for the mouse kidney histological examination and Dr. Christopher Barlow from Monash Proteomics & Metabolomics Facility for the high-resolution mass spectral (HRMS) analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Funding Information: This work was supported by research grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI098771 and AI132154). N.A.P. is an Australia National Health and Medical Research Council (NHMRC) Peter Doherty Fellow. J.Li. is an Australia NHMRC Principal Research Fellow. The authors thank Ms. Jesmin Akter, Hasini Walpola, Jie Lu, and Mr. Yang Hu for their technical support in the pharmacological experiments, the Phenomics Network-Histopathology and Organ Pathology (University of Melbourne, Parkville, VIC, Australia) for the mouse kidney histological examination and Dr. Christopher Barlow from Monash Proteomics & Metabolomics Facility for the high-resolution mass spectral (HRMS) analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
doi = "10.1038/s41467-022-29234-3",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}