A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens

Kade D. Roberts, Yan Zhu, Mohammad A. K. Azad, Mei-Ling Han, Jiping Wang, Lynn Wang, Heidi H. Yu, Andrew S. Horne, Jo-Anne Pinson, David Rudd, Nicolas H. Voelcker, Nitin A. Patil, Jinxin Zhao, Xukai Jiang, Jing Lu, Ke Chen, Olga Lomovskaya, Scott J. Hecker, Philip E. Thompson, Roger L. Nation, Michael N. Dudley, David C. Griffith, Tony Velkov () and Jian Li ()
Additional contact information
Kade D. Roberts: Monash University
Yan Zhu: Monash University
Mohammad A. K. Azad: Monash University
Mei-Ling Han: Monash University
Jiping Wang: Monash University
Lynn Wang: Monash University
Heidi H. Yu: Monash University
Andrew S. Horne: Monash University
Jo-Anne Pinson: Monash University
David Rudd: Monash University
Nicolas H. Voelcker: Monash University
Nitin A. Patil: Monash University
Jinxin Zhao: Monash University
Xukai Jiang: Monash University
Jing Lu: Monash University
Ke Chen: Monash University
Olga Lomovskaya: Qpex Biopharma, Inc.
Scott J. Hecker: Qpex Biopharma, Inc.
Philip E. Thompson: Monash University
Roger L. Nation: Monash University
Michael N. Dudley: Qpex Biopharma, Inc.
David C. Griffith: Qpex Biopharma, Inc.
Tony Velkov: Monash University
Jian Li: Monash University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29234-3

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