Inhibiting Lipopolysaccharide Biogenesis: The More You Know the Further You Go

Gram-negative bacteria are intrinsically resistant to many antibiotics because they are surrounded by an outer membrane that creates a robust permeability barrier. The outer membrane has an unusual asymmetric structure with a periplasmic leaflet composed of phospholipids and an outer leaflet composed of lipopolysaccharides. Because lipid biosynthesis is completed in the inner membrane of these didermic bacteria, these components must be transported across the cell envelope and properly assembled to expand the outer membrane during growth and division. Lipopolysaccharide molecules are transported over a multi-protein transenvelope bridge that is powered by ATP hydrolysis in the cytoplasm. This review discusses how this bridge is assembled and functions and how lipopolysaccharide transport is regulated to ensure balanced growth of all envelope layers. A combination of approaches and new experimental tools have significantly advanced our understanding of this molecular machine and contributed to the development of new antimicrobials that interfere with transport.