![]() (B) LPS is represented with its three components: lipid A, core oligosaccharide, and o-antigen. (A) The cell envelope of gram-negative bacteria is depicted, including the LPS-laden outer leaflet of the outer membrane, inner membrane, and intervening periplasm containing peptidoglycan. The array of enzymes that carry out and regulate the synthesis of O-antigens have been extensively reviewed elsewhere. aeruginosa, is unique in that it concurrently produces an additional form of O-antigen, called common polysaccharide antigen, formed by a homopolymer of D-rhamnose. O-specific antigen (OSA) is the major O-antigen heteropolymer and highly variable among bacterial strains and species, consisting of three to five repeating sugar units that give rise to distinct bacterial serotypes. The O-antigen is covalently attached to the core oligosaccharide and comprises a highly diverse polymer of repeating sugars units. The outer core is covers the inner core, and usually contains additional heptose sugars, some of which are phosphorylated or modified by phosphoethanolamine or pyrophosphoethanolamine. The inner core forms the base of the core oligosaccharide, and usually contains several Kdo (3-deoxy-α-D-manno-octulosonic acid) molecules. The core oligosaccharide, which consists of inner core and outer core, is attached directly to lipid A and usually comprises 10 sugars, typically conserved within a bacterial species. Lipid A is composed of a bisphosphorylated diglucosamine backbone with 4–7 acyl chains. In general, it consists of three components: a phosphorylated glycolipid (known as lipid A), a core oligosaccharide, and an O-antigen sugar chain ( Fig. LPS is a diverse biomolecule with considerable species-to-species chemical variation. The outer membrane is somewhat unusual in biology because it is highly asymmetric due to the distribution of the glycolipid lipopolysaccharide (LPS) in its outer leaflet. The cell envelope comprises an outer membrane, inner membrane, and intervening peptidoglycan layer spanning the periplasm ( Fig. The cell envelope of gram-negative bacteria underpins their ability to withstand harsh environments and survive the immune response of human hosts. Indeed, several potent in vitro inhibitors of essential, well-validated cytoplasmic targets lacked whole cell activity against gram-negative bacterial pathogens due to poor intracellular accumulation. Yet identifying new small molecules with activity against gram-negative bacteria remains challenging due to their impermeable cell envelope and large repertoire of efflux pumps that hinder intracellular accumulation of small molecules. The advent of automated sequencing ushered in the genomic era of antibiotic discovery, allowing for the systematic and comprehensive identification of essential target space as defined by conserved, essential genes across many bacterial species, strains, and clinical isolates. Indeed, the dire need for new therapeutic options compelled the World Health Organization to generate a priority list of antibiotic-resistant bacteria, listing the gram-negative pathogens Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae species as the topmost priority. Gram-negative bacteria pose a major threat to patients with hospital-acquired infections, compromised immune systems, and chronic pulmonary infections due to limited treatment options and their high frequency antibiotic resistance. ![]() In this review, we summarize the LPS biosynthesis and transport pathways and discuss efforts to find small molecule inhibitors against targets within these pathways. Thus, both LPS biosynthesis and transport are attractive pathways to target therapeutically. The biosynthesis and transport of LPS are essential to the viability and virulence of most gram-negative bacteria. Antibiotic discovery efforts against gram-negative bacteria have been hampered by limited intracellular accumulation of xenobiotics, in large part due to the impermeable cell envelope comprising lipopolysaccharide (LPS) in the outer leaflet of the outer membrane, as well as a panoply of efflux pumps. Despite extensive drug discovery campaigns over the past decades, no new antibiotic target class effective against gram-negative bacteria has become available to patients since the advent of the carbapenems in 1985. Gram-negative bacteria pose a major threat to human health in an era fraught with multi-drug resistant bacterial infections.
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