A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threateningAcinetobacter baumannii

Xukai Jiang, Nitin A. Patil, Mohammad A.K. Azad, Hasini Wickremasinghe, Heidi Yu, Jinxin Zhao, Xinru Zhang, Mengyao Li, Bin Gong, Lin Wan, Wendong Ma, Philip E. Thompson, Kai Yang, Bing Yuan, Falk Schreiber, Lushan Wang, Tony Velkov, Kade D. Roberts, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)


Multidrug-resistant Gram-negative bacteria represent a major medical challenge worldwide. New antibiotics are desperately required with ‘old’ polymyxins often being the only available therapeutic option. Here, we systematically investigated the structure-activity relationship (SAR) of polymyxins using a quantitative lipidomics-informed outer membrane (OM) model ofAcinetobacter baumanniiand a series of chemically synthesized polymyxin analogs. By integrating chemical biology and all-atom molecular dynamics simulations, we deciphered how each residue of the polymyxin molecule modulated its conformational folding and specific interactions with the bacterial OM. Importantly, a novel designed polymyxin analog FADDI-287 with predicted stronger OM penetration showed improvedin vitroantibacterial activity. Collectively, our study provides a novel chemical biology and computational strategy to expedite the discovery of new-generation polymyxins against life-threatening Gram-negative ‘superbugs’.

Original languageEnglish
Pages (from-to)12211-12220
Number of pages10
JournalChemical Science
Issue number36
Publication statusPublished - 28 Sep 2021

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