Polymyxins Bind to the Cell Surface of Unculturable Acinetobacter baumannii and Cause Unique Dependent Resistance

Yan Zhu, Jing Lu, Mei-Ling Han, Xukai Jiang, Mohammad A. K. Azad, Nitin A. Patil, Yu-Wei Lin, Jinxin Zhao, Yang Hu, Heidi H. Yu, Ke Chen, John D. Boyce, Rhys A. Dunstan, Trevor Lithgow, Christopher K. Barlow, Weifeng Li, Elena K. Schneider-Futschik, Jiping Wang, Bin Gong, Bjorn SommerDarren J. Creek, Jing Fu, Lushan Wang, Falk Schreiber, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Multidrug-resistant Acinetobacter baumannii is a top-priority pathogen globally and polymyxins are a last-line therapy. Polymyxin dependence in A. baumannii (i.e., nonculturable on agar without polymyxins) is a unique and highly-resistant phenotype with a significant potential to cause treatment failure in patients. The present study discovers that a polymyxin-dependent A. baumannii strain possesses mutations in both lpxC (lipopolysaccharide biosynthesis) and katG (reactive oxygen species scavenging) genes. Correlative multiomics analyses show a significantly remodeled cell envelope and remarkably abundant phosphatidylglycerol in the outer membrane (OM). Molecular dynamics simulations and quantitative membrane lipidomics reveal that polymyxin-dependent growth emerges only when the lipopolysaccharide-deficient OM distinctively remodels with ≥ 35% phosphatidylglycerol, and with “patch” binding on the OM by the rigid polymyxin molecules containing strong intramolecular hydrogen bonding. Rather than damaging the OM, polymyxins bind to the phosphatidylglycerol-rich OM and strengthen the membrane integrity, thereby protecting bacteria from external reactive oxygen species. Dependent growth is observed exclusively with polymyxin analogues, indicating a critical role of the specific amino acid sequence of polymyxins in forming unique structures for patch-binding to bacterial OM. Polymyxin dependence is a novel antibiotic resistance mechanism and the current findings highlight the risk of ‘invisible’ polymyxin-dependent isolates in the evolution of resistance.

Original languageEnglish
Article number2000704
Number of pages13
JournalAdvanced Science
DOIs
Publication statusAccepted/In press - 8 Jun 2020

Keywords

  • Acinetobacter baumannii
  • membrane lipidomics
  • molecular dynamics
  • polymyxin
  • polymyxin-dependent resistance

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