Structure-Interaction Relationship of Polymyxins with the Membrane of Human Kidney Proximal Tubular Cells

Xukai Jiang, Shuo Zhang, Mohammad A. K. Azad, Kade D. Roberts, Lin Wan, Bin Gong, Kai Yang, Bing Yuan, Hemayet Uddin, Jingliang Li, Philip E. Thompson, Tony Velkov, Jing Fu, Lushan Wang, Jian Li

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3 Citations (Scopus)

Abstract

Multidrug-resistant Gram-negative bacteria are a serious global threat to human health. Polymyxins are increasingly used in patients as a last-line therapy to treat infections caused by these life-threatening 'superbugs'. Unfortunately, polymyxin-induced nephrotoxicity is the major dose-limiting factor and understanding its mechanism is crucial for the development of novel, safer polymyxins. Here, we undertook the first all-atom molecular dynamics simulations of the interaction between four naturally occurring polymyxins A1, B1, M1 and colistin A (representative structural variations of the polymyxin core structure) and the membrane of human kidney proximal tubular cells. All polymyxins inserted spontaneously into the hydrophobic region of the membrane where they were retained, although their insertion abilities varied. Polymyxin A1 completely penetrated into the hydrophobic region of the membrane with a unique folded conformation, whereas the other three polymyxins only inserted their fatty acyl tails into this region. Furthermore, local membrane defects and increased water penetration were induced by each polymyxin, which may represent the initial stage of cellular membrane damage. Finally, the structure-interaction relationship of polymyxins was investigated based on atomic interactions at the cell membrane level. The hydrophobicity at positions 6/7 and stereochemistry at position 3 regulated the interactions of polymyxins with the cell membrane. Collectively, our results provide new mechanistic insights into polymyxin-induced nephrotoxicity at the atomic level and will facilitate the development of new-generation polymyxins.

Original languageEnglish
Pages (from-to)2110-2119
Number of pages10
JournalACS Infectious Diseases
Volume6
Issue number8
DOIs
Publication statusPublished - 14 Aug 2020

Keywords

  • membrane
  • molecular dynamics
  • nephrotoxicity
  • polymyxins
  • structure−interaction relationship

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