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Biosynthesis and Genetics of Lipopolysaccharide Core
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
David E. Heinrichs, Chris Whitfield, Miguel A. Valvano
The typical core oligosaccharide (core OS) of lipopolysaccharide (LPS) is a phosphorylated heterooligosaccharide of less than 15 sugars, whose structure is described in detail elsewhere in this volume. In some gram-negative bacteria, LPS can terminate with the core OS to form so-called rough LPS (R-LPS). In others, the core OS can be capped by an O-polysaccharide (O-PS) to form smooth LPS (S-LPS). The “smooth” and “rough” terminology originates from observations that colonies of O-PS-containing strains often have a smooth appearance on solid media, whereas colonies of mutants that do not produce an O-PS tend to have a rough surface. Production of an O-PS is implicated in resistance to host defense mechanisms, such as complement-mediated serum killing, and has been shown to increase the pathogenicity of many gram-negative species. However, some pathogenic organisms including members of the genera Neisseria, Haemophilus, Bordetella, Branham ella, and Cam pylobacter, among others, lack O-PS but produce lipooligosaccharide (LOS) instead (see Ref. 1). Therefore, while the importance of the O-PS should certainly not be overlooked, it is clearly not an indispensable component of the pathogenicity and survival of some organisms.
A study of Rose Bengal against a 2-keto-3-deoxy-d -manno-octulosonate cytidylyltransferase as an antibiotic candidate
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Suwon Kim, Seri Jo, Mi-Sun Kim, Dong Hae Shin
The 2-keto-3-deoxy-manno-octulosonic acid (KDO) which is an eight carbon acidic sugar composing the lipopolysaccharide (LPS) has a vital role in keeping outer membrane (OM) integrity and viability of most Gram-negative bacteria1,2. The KDO biosynthesis pathway consists of six enzymes: Ribose-5-phosphate isomerase (RpiA)3; d-arabinose-5-phosphate isomerase (KpsF)4; KDO-8-phosphate synthase (KdsA)5; KDO-8-phosphate phosphatase (YrbI)6; 2-keto-3-deoxy-d-manno-octulosonate cytidylyltransferase (KdsB), and glycosyltransferase (WaaA) which transfers the KDO from cytidine 5′-monophospho-2-keto-3-deoxy-manno-octulosonic acid (CMP-KDO) to the lipid A7. In LPS, KDO molecules are important to connect the core oligosaccharide with the lipid A8–10. Therefore, the KDO biosynthesis pathway has been considered as the potential target for the advanced antibiotics against Gram-negative bacteria1,11.
A study of inhibitors of d -glycero-β-d -manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei as a potential antibiotic target
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Suwon Kim, Seri Jo, Mi-Sun Kim, Dong Hae Shin
Lipopolysaccharide (LPS) is an amphipathic glycolipid in the outer membrane of Gram-negative bacteria. Through electrostatic interactions with outer membrane proteins and divalent cations of phosphate groups on the heptoses, LPS maintains membrane stability and limits permeability of the bacterial outer membrane9–11. There are three parts composing the LPS layer: disaccharyl–lipid complex (lipid A); a core oligosaccharide; and a repeating oligosaccharide (O-antigen)12. The core oligosaccharide can be partitioned into an inner core consisting of 3-deoxy-d-manno-octulosonic acid (KDO) and heptoses, and an outer core containing hexoses and N-acetyl-d-hexosamine13.
An update on endotoxin neutralization strategies in Gram-negative bacterial infections
Published in Expert Review of Anti-infective Therapy, 2021
Klaus Brandenburg, Andra B Schromm, Günther Weindl, Lena Heinbockel, Wilmar Correa, Karl Mauss, Guillermo Martinez de Tejada, Patrick Garidel
The large diversity of Gram-negative bacteria contains many subgroups or particular species with high infection potential such as Pseudomonas aeruginosa, Acinetobacter baumanii, and Salmonella spp., and from the family of Enterobacteriaceae germs such as those from Enterobacter spp., Klebsiella pneumoniae, and Escherichia coli, for the latter two in particular the ESBL (extended-spectrum beta-lactam) resistant mutants [1]. For the listed bacteria there is an urgent medical need to develop new antibiotics as has been demanded by the WHO [2]. These and other observations indicate that in the first place, Gram-negative bacteria should be in the focus of developing antimicrobials to inhibit infections, in particular, to reduce the still increasing number of patients suffering from sepsis with high lethality. Therefore, new therapeutic approaches must address in each case targeting of endotoxins (LPS, lipopolysaccharides), whether as constituent of the outer leaflet of the outer membrane or after release of the bacteria [3]. LPS as main component of the outer leaflet of the outer membrane of the bacteria consists of a hydrophobic part, the membrane-anchored lipid A moiety, having a bisphosphoryl diglucosamine backbone to which up to seven acyl chains are ester- or amide-linked. To the lipid A part a core oligosaccharide is linked, with a length according to the kind of mutant (deep rough mutant Re with the shortest and Ra mutant with a complete core). Additionally, in the case of wild-type LPS (smooth forms) an O-antigen is present with high variability of the chemical structure for different bacteria. Important is the observation that nearly for all biological activity the lipid A part is responsible.