4.6 Article

Discovering interrelated natural mutations of efflux pump KmrA from Klebsiella pneumoniae that confer increased multidrug resistance

期刊

PROTEIN SCIENCE
卷 31, 期 6, 页码 -

出版社

WILEY
DOI: 10.1002/pro.4323

关键词

efflux pump; Klebsiella pneumoniae; major facilitator superfamily; molecular dynamics

资金

  1. Project of Beijing Municipal Commission of Education [KZ201911417049]
  2. Beijing Municipal Education Commission Technology Plan [KM202011417006]

向作者/读者索取更多资源

The study investigated the natural mutations of the KmrA gene in Klebsiella pneumoniae and identified two variants that enhanced multidrug resistance. Through molecular dynamics simulations, it was revealed that these mutations increased drug export efficiency by strengthening the interactions between KmrA and water as well as the cell membrane, and promoting conformational changes.
Klebsiella pneumoniae is a notorious pathogen that can cause multiorgan infections, which is difficult to treat mainly due to the widely distributed efflux pumps. Our previous research discovered the upregulation of efflux pump KmrA conferred enhanced antibiotic resistance, while the export mechanism and its natural mutations across K. pneumoniae isolates remain unclear. Herein, we analyzed the natural mutations of KmrA across 830 K. pneumoniae genomes to discover interrelated amino-acid substitutions (simultaneously occurred substitutions) that increase drug export. We identified two variants that contain triple amino-acid substitutions near the periplasmic side and then confirmed their roles in enhancing multidrug resistance of recombinant K. pneumoniae strains. Molecular dynamics simulations were conducted to illustrate the reason for their promoted export efficiencies. Our data indicated the triple substitutions resulted in KmrA's both stronger hydrophilic interaction with water and hydrophobic interaction with membrane. Moreover, these substitutions promoted the flexibilities of KmrA that could facilitate the conformational switch. In parallel, stronger ionic interactions (salt bridges) at cytoplasmic side also suggested the higher possibilities for the reciprocal movements. Collectively we demonstrated the potential risk of the interrelated natural mutations in efflux pump to antibiotic resistance of K. pneumoniae and provided insights into the mechanism of the enhanced drug export.

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