Abstract
The lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria is primarily composed of the glycolipid lipopolysaccharide (LPS), which serves to form a protective barrier against hydrophobic toxins and many antibiotics. LPS is comprised of three regions: the lipid A membrane anchor, the nonrepeating core oligosaccharide, and the repeating O-antigen polysaccharide. The lipid A portion is also referred to as endotoxin as its overstimulation of the toll-like receptor 4 during systemic infection precipitates potentially fatal septic shock. Because of the importance of LPS for the viability and virulence of human pathogens, understanding how LPS is synthesized and transported to the outer leaflet of the outer membrane is important for developing novel antibiotics to combat resistant Gram-negative strains. The following review describes the current state of our understanding of the proteins responsible for the synthesis and transport of LPS with an emphasis on the contribution of protein structures to our understanding of their functions. Because the lipid A portion of LPS is relatively well conserved, a detailed description of the biosynthetic enzymes in the Raetz pathway of lipid A synthesis is provided. Conversely, less well-conserved biosynthetic enzymes later in LPS synthesis are described primarily to demonstrate conserved principles of LPS synthesis. Finally, the conserved LPS transport systems are described in detail.
Highlights
Gram-negative bacteria are distinguished from Grampositive bacteria by the secondary lipid bilayer that surrounds their peptidoglycan cell wall [1]
LPS is a glycolipid composed of a lipid A membrane anchor, a core oligosaccharide, and a repeating O antigen polysaccharide (Figure 1) [1, 5]. is layer of LPS provides a permeability barrier to environmental toxins. When this layer of LPS is disrupted by invasion of phospholipids [2], loss of LPS synthesis or transport [6], or loss of glycosylation [7], the bacteria show increased sensitivity to hydrophobic toxins, such as detergent or bile salts or antibiotics
Because of the severity of this condition, rapid treatment with broad-spectrum antibiotics before the causative bacteria can be identified is recommended for patients with sepsis [15]. e highly conserved and essential enzymes involved in the synthesis of the lipid A portion of LPS are promising targets for the development of new broad-spectrum antibiotics to treat sepsis and infections by antimicrobial-resistant Gram-negative strains [1, 7, 17, 18]
Summary
Gram-negative bacteria are distinguished from Grampositive bacteria by the secondary lipid bilayer that surrounds their peptidoglycan cell wall [1]. Activation of TLR4 by LPS leads to the production and secretion of proinflammatory cytokines and type I interferon [9, 14]. While this response is beneficial for clearing small bacterial. E highly conserved and (in most cases) essential enzymes involved in the synthesis of the lipid A portion of LPS are promising targets for the development of new broad-spectrum antibiotics to treat sepsis and infections by antimicrobial-resistant Gram-negative strains [1, 7, 17, 18] Because of the severity of this condition, rapid treatment with broad-spectrum antibiotics before the causative bacteria can be identified is recommended for patients with sepsis [15]. e highly conserved and (in most cases) essential enzymes involved in the synthesis of the lipid A portion of LPS are promising targets for the development of new broad-spectrum antibiotics to treat sepsis and infections by antimicrobial-resistant Gram-negative strains [1, 7, 17, 18]
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