Proteomic Changes of Klebsiella pneumoniae in Response to Colistin Treatment and crrB Mutation-Mediated Colistin Resistance

Lang Sun, Pernille Kronholm Rasmussen, Yinlei Bai, Xiulan Chen, Tanxi Cai, Jifeng Wang, Xiaojing Guo, Zhensheng Xie, Xiang Ding, Lili Niu, Nali Zhu, Xuefu You, Finn Kirpekar*, Fuquan Yang

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Polymyxins are increasingly used as the critical last-resort therapeutic options for multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance has increased gradually over the past few years. Although studies on polymyxin mechanisms are expanding, systemwide analyses of the underlying mechanism for polymyxin resistance and stress response are still lacking. To understand how Klebsiella pneumoniae adapts to colistin (polymyxin E) pressure, we carried out proteomic analysis of a K. pneumoniae strain cultured with different concentrations of colistin. Our results showed that the proteomic responses to colistin treatment in K. pneumoniae involve several pathways, including (i) gluconeogenesis and the tricarboxylic acid (TCA) cycle, (ii) arginine biosynthesis, (iii) porphyrin and chlorophyll metabolism, and (iv) enterobactin biosynthesis. Interestingly, decreased abundances of class A β-lactamases, including TEM, SHV-11, and SHV-4, were observed in cells treated with colistin. Moreover, we present comprehensive proteome atlases of paired polymyxin-susceptible and -resistant K. pneumoniae strains. The polymyxin-resistant strain Ci, a mutant of K. pneumoniae ATCC BAA 2146, showed a missense mutation in crrB. This crrB mutant, which displayed lipid A modification with 4-amino-4-deoxy-L-arabinose (L-Ara4N) and palmitoylation, showed striking increases in the expression of CrrAB, PmrAB, PhoPQ, ArnBCADT, and PagP. We hypothesize that crrB mutations induce elevated expression of the arnBCADTEF operon and pagP via PmrAB and PhoPQ. Moreover, the multidrug efflux pump KexD, which was induced by crrB mutation, also contributed to colistin resistance. Overall, our results demonstrated proteomic responses to colistin treatment and the mechanism of CrrB-mediated colistin resistance, which may offer valuable information on the management of polymyxin resistance.

Original languageEnglish
Article numbere02200-19
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number6
ISSN0066-4804
DOIs
Publication statusPublished - Jun 2020

Keywords

  • CrrB mutation
  • Klebsiella pneumoniae
  • Lipid A modification
  • Multidrug efflux pump KexD
  • Polymyxin resistance
  • Proteomics
  • β-lactamase

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