Lipopolysaccharide transport protein D (LptD) and Lipid A export ATP-binding cassette transporter MsbA (MsbA) (LptD/MsbA)

The Lipopolysaccharide (LPS) transport system, comprising the inner membrane flippase MsbA and the outer membrane translocon LptD, is essential for the biogenesis of the Gram-negative bacterial outer membrane (UniProt P0ADV1, P31554). MsbA is an ATP-binding cassette (ABC) transporter that translocates Lipid A-core from the cytoplasmic to the periplasmic leaflet of the inner membrane (Zhang et al., Nature 2018). LptD, in complex with LptE, forms a 26-stranded beta-barrel that facilitates the final insertion of LPS into the outer leaflet of the outer membrane (Botos et al., Structure 2016). This pathway is a critical target for novel antibiotics because its disruption leads to the accumulation of toxic LPS intermediates and loss of membrane integrity, resulting in bacterial cell death (Sperandeo et al., J. Bacteriol. 2008). Therapeutic candidates like Murepavadin target LptD, while small molecules such as G907 and G001 have been developed to inhibit MsbA (Martin-Loeches et al., Lancet Infect Dis 2018; Zhang et al., Nature 2018). Despite their potential, the development of these drugs faces challenges including the rapid emergence of resistance mutations and specific safety concerns like the nephrotoxicity observed with certain peptide-based LptD inhibitors.

Other names

Lipopolysaccharide transport systemLpt pathwayLipid A flippase (MsbA)Outer membrane protein LptDLptDE complexLPS export machinery

Inhibition of the lipopolysaccharide (LPS) transport pathway by blocking either the inner membrane flippase MsbA or the outer membrane translocon LptD, preventing the assembly of the bacterial outer membrane.