Lipid trafficking across the Gram-negative cell envelope

The outer membrane (OM) of Gram-negative bacteria exhibits unique lipid asymmetry, with lipopolysaccharides (LPS) residing in the outer leaflet and phospholipids (PLs) in the inner leaflet. This asymmetric bilayer protects the bacterium against intrusion of many toxic substances, including antibiotics and detergents, yet allows acquisition of nutrients necessary for growth. To build the OM and ensure its proper function, the cell produces OM constituents in the cytoplasm or inner membrane and transports these components across the aqueous periplasmic space separating the two membranes. Of note, the processes by which the most basic membrane building blocks, i.e. PLs, are shuttled across the cell envelope remain elusive. This review highlights our current understanding (or lack thereof) of bacterial PL trafficking, with a focus on recent developments in the field. We adopt a mechanistic approach and draw parallels and comparisons with well-characterized systems, particularly OM lipoprotein and LPS transport, to illustrate key challenges in intermembrane lipid trafficking. Pathways that transport PLs across the bacterial cell envelope are fundamental to OM biogenesis and homeostasis and are potential molecular targets that could be exploited for antibiotic development.