The article describes the discovery and structural analysis of a new class of antibiotics that target the lipopolysaccharide (LPS) transport machinery in *Acinetobacter*. These antibiotics, particularly macrocyclic peptides, are effective against *Acinetobacter* strains, including carbapenem-resistant *A. baumannii*. The antibiotics trap a substrate-bound conformation of the LPS transporter, preventing LPS from reaching the outer membrane. The study uses structural, biochemical, and genetic approaches to demonstrate that the inhibitors recognize a composite binding site formed by the LPS transporter and its substrate. The findings reveal a novel mechanism of lipid transport inhibition and identify a druggable conformation of the LPS transporter, providing a foundation for extending this class of antibiotics to other Gram-negative pathogens. The research also highlights the importance of LPS structure and the role of specific residues in the LPS transporter for drug binding and efficacy.The article describes the discovery and structural analysis of a new class of antibiotics that target the lipopolysaccharide (LPS) transport machinery in *Acinetobacter*. These antibiotics, particularly macrocyclic peptides, are effective against *Acinetobacter* strains, including carbapenem-resistant *A. baumannii*. The antibiotics trap a substrate-bound conformation of the LPS transporter, preventing LPS from reaching the outer membrane. The study uses structural, biochemical, and genetic approaches to demonstrate that the inhibitors recognize a composite binding site formed by the LPS transporter and its substrate. The findings reveal a novel mechanism of lipid transport inhibition and identify a druggable conformation of the LPS transporter, providing a foundation for extending this class of antibiotics to other Gram-negative pathogens. The research also highlights the importance of LPS structure and the role of specific residues in the LPS transporter for drug binding and efficacy.