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

Abstract

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.