Lipopolysaccharide transport system (Lpt system) (Lpt)

The Lipopolysaccharide transport system (Lpt system) is a specialized protein machinery in Gram-negative bacteria responsible for moving lipopolysaccharide (LPS) molecules from the inner membrane to the cell surface (Sperandeo et al., 2019, PMID: 31110064). This system consists of seven essential proteins that form a bridge across the periplasmic space, with the LptD-LptE complex serving as the final translocon located in the outer membrane (UniProt P0ADV1). LPS is a critical structural component that provides an impermeable barrier against many antibiotics and environmental stressors; therefore, disrupting its transport is lethal to the bacteria. Therapeutic strategies targeting these outer membrane components, such as the peptidomimetic drug Murepavadin, aim to inhibit LptD, causing LPS to accumulate in the periplasm and compromising the integrity of the bacterial cell envelope (Srinivas et al., 2010, PMID: 20167782). This target is of high interest for treating multi-drug resistant infections, particularly those caused by Pseudomonas aeruginosa. However, clinical development of LptD inhibitors has faced significant challenges, including concerns over systemic toxicity, specifically nephrotoxicity, and the potential for rapid resistance development (Spexis, 2023). Overall, the Lpt system represents a validated but difficult-to-drug pathway for the next generation of Gram-negative specific antibiotics.

Other names

LPS transport machineryLpt complexLptD-LptE transloconLipopolysaccharide assembly machineryLipopolysaccharide biosynthesis-related outer membrane components

Inhibition of the LptD-LptE complex prevents the translocation of lipopolysaccharide from the periplasm to the outer leaflet of the outer membrane, leading to membrane defects and bacterial lysis (Srinivas et al., 2010, PMID: 20167782).