PhoP-regulated VirK acts as an accessory factor to maintain virulence in polymyxin-resistant Klebsiella pneumoniae

  • Nucleic Acids Res. 2026 Apr 23;54(8):gkag290. doi: 10.1093/nar/gkag290.
Haibin Li  1 ,  Longyang Jin  1 ,  Penghe Wang  2 ,  Ruobing Wang  1 ,  Qi Wang  1 ,  Xiukun Wang  2 ,  Congran Li  2 ,  Xuefu You  2  3 ,  Hui Wang  1  4
Affiliations
  • 1. Department of Clinical Laboratory, Peking University People's Hospital, Beijing, 100044, China.
  • 2. Beijing Key Laboratory of Technology and Application for Anti-infective New Drugs Research and Development, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 3. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 4. Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China.
PMID: 42033226 DOI: 10.1093/nar/gkag290
Abstract

The genetic connection between virulence and Antibiotic resistance remains poorly understood. Our previous RNA-Seq analysis of a polymyxin-resistant Klebsiella pneumoniae ATCC BAA2146 mutant identified a highly expressed VirK/YbjX family gene (kpn2146_RS17285), encoding a conserved membrane protein, designated virK (virulence required for Klebsiella pneumoniae). While PhoP-dependent Antibiotic resistance is mediated through established pathways such as arn/pmr, we identify VirK as a PhoP-regulated factor specifically contributing to virulence. VirK localizes to the outer membrane and, although not involved in lipopolysaccharide modification, its deletion modestly reduced Bacterial virulence in a mouse systemic Infection model. Transcriptional and electrophoretic mobility shift assays demonstrated that virK is directly activated by the PhoP protein. A strong positive correlation between virK and phoP expression (r = 0.98) was also observed in multidrug-resistant clinical isolates. Since the PhoP/PhoQ two-component system mediates polymyxin resistance, its direct regulation of VirK uncovers an adaptive mechanism coupling enhanced virulence with Antibiotic resistance. These findings reveal a previously unrecognized PhoP/VirK regulatory pathway that contributes to pathogenicity in polymyxin-resistant Klebsiella pneumoniae, offering new insights into Bacterial evolution and suggesting that targeting PhoP/PhoQ could provide an effective strategy to combat multidrug-resistant K. pneumoniae infections.

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