Lipopolysaccharide-assembly protein LptD (LptD)

Lipopolysaccharide-assembly protein LptD is an essential outer membrane protein in Gram-negative bacteria that facilitates the final step of lipopolysaccharide (LPS) transport to the cell surface [1.1.1, 1.4.2]. It forms a functional translocon complex with the lipoprotein LptE, characterized by a "plug-and-barrel" structure where LptE resides within the 26-stranded beta-barrel of LptD [1.1.4, 1.4.3]. This complex is responsible for inserting LPS into the outer leaflet of the outer membrane, a process critical for maintaining the bacterial permeability barrier and protecting against environmental stressors and antibiotics [1.1.3, 1.2.1]. Due to its essentiality and accessibility on the bacterial surface, LptD is a major target for novel antibacterial drug development, particularly against multidrug-resistant pathogens like Pseudomonas aeruginosa [1.2.2, 1.2.3]. Drugs such as Murepavadin (POL7080) act by binding to the periplasmic domain of LptD, thereby blocking LPS assembly and causing membrane disruption and cell death [1.2.3, 1.3.3]. However, clinical development has been hindered by safety concerns, most notably nephrotoxicity observed in late-stage trials [1.3.3, 1.3.5]. Despite these challenges, LptD remains a high-value target for narrow-spectrum antibiotics and potential combination therapies aimed at sensitizing bacteria to existing drugs [1.2.1, 1.3.2].

Other names

ImpOstAOrganic solvent tolerance protein AIncreased membrane permeability protein

Inhibition of the LptDE translocon complex, which prevents the assembly and insertion of lipopolysaccharide (LPS) into the outer leaflet of the bacterial outer membrane, leading to loss of membrane integrity and cell death.