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<p><i>Acinetobacter baumannii</i> is a critical-priority pathogen with increasing antibiotic resistance. Here, we define the mechanism of abaucin, a first-in-class narrow-spectrum antibiotic that selectively targets <i>A. baumannii</i> by inhibiting its essential lipoprotein transporter, LolDF. Extending prior studies of archived strains, we demonstrate potent activity against clinically isolated carbapenem-resistant <i>A. baumannii</i> (CRAB) strains both in vitro and in a murine pneumonia model. Cryo-EM structures of abaucin-bound LolDF reveal symmetric binding of two abaucin molecules within the LolDF cavity, which lock the transporter in a non-productive, outward-open conformation. Biochemical and structural analyses show that abaucin does not block substrate binding but instead traps the substrate-loaded transporter and prevents transfer to LolA. Together, these findings uncover a unique symmetry-enabled conformation-hijacking mechanism and establish LolDF as a tractable target for precision antibiotic development.</p>

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Conformational hijacking of lipoprotein transporter LolDF enables precision antimicrobial activity against Acinetobacter baumannii

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Jie Pang,
  • Yawen Chen,
  • Dengcheng Zhou,
  • Lijue Wang,
  • Yuling Xiao,
  • Zhibo Zhang,
  • Zhaxi Zerang,
  • Maolin Duan,
  • Lele Zhang,
  • Xiang Gu,
  • Min Xiao,
  • Jingyu Wang,
  • Hui Cui,
  • Aijia Wen,
  • Shouyue Zhang,
  • Yiwen Zhang,
  • Binwu Ying,
  • Liang Ouyang,
  • Xiawei Wei,
  • Bi-Sen Ding,
  • Xiaodi Tang,
  • Haohao Dong

摘要

Acinetobacter baumannii is a critical-priority pathogen with increasing antibiotic resistance. Here, we define the mechanism of abaucin, a first-in-class narrow-spectrum antibiotic that selectively targets A. baumannii by inhibiting its essential lipoprotein transporter, LolDF. Extending prior studies of archived strains, we demonstrate potent activity against clinically isolated carbapenem-resistant A. baumannii (CRAB) strains both in vitro and in a murine pneumonia model. Cryo-EM structures of abaucin-bound LolDF reveal symmetric binding of two abaucin molecules within the LolDF cavity, which lock the transporter in a non-productive, outward-open conformation. Biochemical and structural analyses show that abaucin does not block substrate binding but instead traps the substrate-loaded transporter and prevents transfer to LolA. Together, these findings uncover a unique symmetry-enabled conformation-hijacking mechanism and establish LolDF as a tractable target for precision antibiotic development.