Coarse-grained simulations uncover Gram-negative bacterial defense against polymyxins by the outer membrane

Xukai Jiang, Yuliang Sun, Kai Yang, Bing Yuan, Tony Velkov, Lushan Wang, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)


The outer membrane (OM) of Gram-negative bacteria is a formidable barrier against antibiotics. Understanding the structure and function of the OM is essential for the discovery of novel membrane-acting agents against multidrug-resistant Gram-negative pathogens. However, it remains challenging to obtain three-dimensional structure of bacterial membranes using crystallographic approaches, which has significantly hindered the elucidation of its interaction with antibiotics. Here, we developed an asymmetric OM model consisting of rough lipopolysaccharide (LPS) and three key types of phospholipids. Using coarse-grained molecular dynamics simulations, we investigated the interaction dynamics of LPS-containing OM with the polymyxins, a last-line class of antibiotics against Gram-negative ‘superbugs’. We discovered that polymyxin molecules spontaneously penetrated the OM core sugar region where most were trapped before entering the lipid A region. Examination of the free energy profile of polymyxin penetration revealed a major free energy barrier at the LPS inner core and lipid A interface. Further analysis revealed calcium ions predominantly distributed in the inner core region and mediated extensive cross-linking interactions between LPS molecules, thereby inhibiting the penetration of polymyxins into the hydrophobic region of the OM. Collectively, our results provide novel mechanistic insights into an intrinsic defense of Gram-negative bacteria to polymyxins and may help identify new antimicrobial targets.

Original languageEnglish
Pages (from-to)3885-3891
Number of pages7
JournalComputational and Structural Biotechnology Journal
Publication statusPublished - 2021


  • Antibiotic resistance
  • LPS
  • Molecular dynamics simulations
  • Outer membrane
  • Polymyxin

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