Localization of lipoprotein CDE ABC transporter complex (LolCDE)

The Localization of lipoprotein CDE (LolCDE) ABC transporter complex is an essential molecular machinery in Gram-negative bacteria responsible for the first step of the Lol pathway, which traffics lipoproteins from the inner membrane to the outer membrane [2, 8]. The complex is composed of three subunits: LolC, LolE, and two copies of the ATPase subunit LolD, which together function as a molecular extruder to recognize and release mature triacylated lipoproteins into the periplasm for capture by the chaperone LolA [5, 6]. Because this transport process is vital for maintaining the structural integrity and biogenesis of the bacterial outer membrane, LolCDE is a highly attractive target for the development of novel antibiotics [1, 14]. Recent therapeutic advancements include the discovery of lolamicin, a selective small-molecule inhibitor that demonstrates potent efficacy against pathogenic Gram-negative bacteria in models of sepsis and pneumonia while sparing the commensal gut microbiome [1]. Other experimental inhibitors, such as the pyrrolopyrimidinedione G0507 and various pyridineimidazoles, have been shown to block lipoprotein release, leading to lethal accumulation of proteins like Lpp in the inner membrane and triggering a robust cellular stress response [2, 12, 15]. Understanding the structural transitions of LolCDE during ATP hydrolysis has provided critical insights into how these drugs disrupt the essential mechanical movement required for substrate extrusion [6, 9].

Other names

LolCDE complexLipoprotein-releasing systemLolCDE transporterInner membrane lipoprotein-releasing system

Inhibition of lipoprotein release from the inner membrane to the outer membrane by competitively binding to the LolCDE complex or uncoupling ATPase activity from transport, leading to the accumulation of lipoproteins in the inner membrane and subsequent bacterial cell death [1, 2, 12].