An Intelligent Strategy with All-Atom Molecular Dynamics Simulations for the Design of Lipopeptides against Multidrug-Resistant Pseudomonas aeruginosa

Xukai Jiang, Meiling Han, Kevin Tran, Nitin A. Patil, Wendong Ma, Kade D. Roberts, Min Xiao, Bjorn Sommer, Falk Schreiber, Lushan Wang, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)


Multidrug-resistant Gram-negative bacteria seriously threaten modern medicine due to the lack of efficacious therapeutic options. Their outer membrane (OM) is an essential protective fortress to exclude many antibiotics. Unfortunately, current structural biology methods are not able to resolve the membrane structure and it is difficult to examine the specific interaction between the OM and small molecules. These limitations hinder mechanistic understanding of antibiotic penetration through the OM and antibiotic discovery. Here, we developed biologically relevant OM models by quantitatively determining membrane lipidomics of Pseudomonas aeruginosa and elucidated how lipopolysaccharide modifications and OM vesicles mediated resistance to polymyxins. Supported by chemical biology and pharmacological assays, our multiscale molecular dynamics simulations provide an intelligent platform to quantify the membrane-penetrating thermodynamics of peptides and predict their antimicrobial activity. Through experimental validations with our in-house polymyxin analogue library, our computational strategy may have significant potential in accelerating the discovery of lipopeptides against bacterial "superbugs".

Original languageEnglish
Pages (from-to)10001-10013
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - 28 Jul 2022

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