Inhibition of arabinose 5-phosphate isomerase. An approach to the inhibition of bacterial lipopolysaccharide biosynthesis

Bigham, Eric C.; Gragg, Charles E.; Hall, William R.; Kelsey, John E.; Mallory, W. Revill; Richardson, D.C.; Benedict, Charles D.; Ray, Paul H.

doi:10.1021/jm00372a003

Cited by 37 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lipid A biosynthesis occurs on the cytosolic surface of the inner membrane and is catalyzed by 10 unique enzymes. Arabinose-5-phosphate isomerase catalyzes first step in the synthesis of lipopolysaccharide and has been used as a drug target in many pathogens [27,[48][49][50]. UDP-3-O- [3-hydroxymyristoyl] N-acetylglucosamine deacetylase catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis, and has been exploited as a drug target by various workers [31,32].…”

Section: Arabinose-5-phosphate Isomerase and Udp-3-o-[3hydroxymyristomentioning

confidence: 99%

In Silico Identification of Novel Drug Targets in Acinetobacter Baumannii by Subtractive Genomic Approach

Goyal

Citu

Singh

2018

Asian J Pharm Clin Res

View full text Add to dashboard Cite

Objective: Multiple drug resistance (MDR) in bacteria, particularly Gram-negative bacilli, has significantly hindered the treatment of infections caused by these bacteria. This results in the need for identifying new drugs and drug targets for these bacteria. The objective of this study was to identify novel drug targets in Acinetobacter baumannii which has emerged as a medically important pathogen due to an increasing number of infections caused by it and its MDR property.Methods: In our study, we implemented in silico subtractive genomics approach to identify novel drug targets in A. baumannii American type culture collection 17978. Various databases and online software were used to build a systematic workflow involving comparative genomics, metabolic pathways analysis, and drug target prioritization to identify pathogen-specific novel drug targets.Results: First, 458 essential proteins were retrieved from a database of essential genes, and by performing BLASTp against Homo sapiens, 246 human non-homologous essential proteins were selected of 458 proteins. Metabolic pathway analysis performed by Kyoto Encyclopedia of Genes and Genomes–Kyoto Automatic Annotation Server revealed that these 246 essential non-homologous proteins were involved in 66 metabolic pathways. Among these metabolic pathways, 12 pathways were found to be unique to Acinetobacter that involved 37 non-homologous essential proteins. Of these essential non-homologous proteins, 19 proteins were found in common as well as unique metabolic pathways and only 18 proteins were unique to Acinetobacter. Finally, these target proteins were filtered to 9 potential targets, based on subcellular localization and assessment of druggability using Drug bank, ChEMBL, and literature.Conclusion: Our study identified nine potential drug targets which are novel targets in A. baumannii and can be used for designing drugs against these proteins. These drugs will be pathogen specific with no side effects on human host, as the potential drug targets are human non-homologous.

show abstract

Section: Arabinose-5-phosphate Isomerase and Udp-3-o-[3hydroxymyristomentioning

confidence: 99%

In Silico Identification of Novel Drug Targets in Acinetobacter Baumannii by Subtractive Genomic Approach

Goyal

Citu

Singh

2018

Asian J Pharm Clin Res

View full text Add to dashboard Cite

show abstract

“…These compounds were reported to be bacteriostatic in vitro . Other synthetic compounds directed against another enzyme involved in Kdo biosynthesis, namely arabinose‐5‐phosphate isomerase, inhibited the enzyme but did not show antibacterial activity [25].…”

mentioning

confidence: 99%

Isolation and structural analysis of phosphorylated oligosaccharides obtained from Escherichia coli J‐5 lipopolysaccharide

Müller‐Loennies

Holst²,

Lindner

et al. 1999

European Journal of Biochemistry

View full text Add to dashboard Cite

The chemical structure of the phosphorylated lipopolysaccharide (LPS) of Escherichia coli J-5 was investigated because it is of biomedical interest in the context of septic shock, a syndrome often encountered in nosocomial infections with gram-negative pathogens. The successive de-O-acylation and de-N-acylation of J-5 LPS yielded phosphorylated oligosaccharides which represent the complete carbohydrate backbone. Five compounds were separated by high-performance anion-exchange chromatography and analysed by one-dimensional and twodimensional homonuclear and heteronuclear 1 H-NMR, 13 C-NMR and 31 P-NMR spectroscopy. The main product was a nonasaccharide of the structurewherein all sugars are present as d-pyranoses. Hep and Kdo represent l-glycero-d-manno-heptose and 3-deoxy-d-manno-oct-2-ulosonic acid, respectively. In addition, two octasaccharides and two heptasaccharides were isolated that were partial structures of the nonasaccharide. In one octasaccharide the terminal a-d-GlcpN was missing and an additional phosphate group linked to O4 of the branched heptose was present, whereas in the other octasaccharide the sidechain Kdo was missing. In both heptasaccharides the side-chain a-d-GlcpN-(137)-l-a-d-Hepp-disaccharide was absent; they differed in their phosphate substitution. Whereas both heptasaccharides contained two phosphates in the lipid-A backbone (b-1,6-linked GlcpN-disaccharide at the reducing end) and one phosphate group at O4 of the first heptose, only one of them was additionally substituted with phosphate at O4 of the second heptose.Keywords: antibodies; biosynthesis; E. coli J-5; lipopolysaccharide; MALDI-TOF MS; phosphorylation; RcP + -chemotype.Lipopolysaccharide (LPS, endotoxin) is the major component of the outer membrane of gram-negative bacteria and is responsible for many of the pathophysiological effects observed during infections with gram-negative pathogens that may lead to septic shock and death [1,2]. Enterobacterial LPS consists of three domains, i.e. lipid A, core region and O-specific chain [1,3], of which lipid A is structurally the most conserved among different pathogenic bacteria [4] and represents the toxic principle of LPS [5]. Despite decades of intensive research and a great demand for alternatives, conventional antibiotic treatment still remains the main weapon of clinicians in the treatment of such infections. As the toxic effects exerted by LPS are independent of the viability of bacteria and considering the increasing resistance of pathogenic bacteria to antibiotics, the search for alternative strategies is of major importance. One of the most promising approaches for the immunotherapy of septic shock is passive immunization with antibodies that are directed against the conserved regions of LPS, i.e. lipid A and the core region. Such antibodies are expected to be cross-reactive with different gramnegative pathogens and might therefore be cross-protective. The induction of such antibodies could be achieved by immunization with lipid A presented in an appropriate form or mut...

show abstract

“…All reagents and solvents were of commercial grade and used according to supplier instructions unless otherwise mentioned. [20,23]. DMF was added (117 L, 110 mg, 1.51 mmol) to a solution of oxalyl chloride (129 L, 194 mg, 1.52 mmol) in CH 2 Cl 2 (4 mL) at 0 ∘ C, and the mixture was stirred for 12 min.…”

Section: Resultsmentioning

confidence: 99%

Convenient Synthesis of 1,4-Dideoxy-1,4-imino-D-ribitol from D-Ribose

Oba

Kawaji

Kushima

et al. 2013

Journal of Chemistry

View full text Add to dashboard Cite

This paper describes a convenient synthesis of 1,4-dideoxy-1,4-imino-D-ribitol (DRB) from D-ribose. L-Lyxonolactone, a key intermediate in this synthesis, was prepared by base-promoted hydrolysis of a 5-chlorinated D-ribonolactone derivative with inversion of configuration at the C-4 position. Cyclization of the generated dimesylated L-lyxitol with benzylamine proceeded with another configurational inversion at C-4 to afford the D-ribo-configured pyrrolidine system, which upon deprotection gave DRB.

show abstract

Inhibition of arabinose 5-phosphate isomerase. An approach to the inhibition of bacterial lipopolysaccharide biosynthesis

Cited by 37 publications

References 0 publications

In Silico Identification of Novel Drug Targets in Acinetobacter Baumannii by Subtractive Genomic Approach

In Silico Identification of Novel Drug Targets in Acinetobacter Baumannii by Subtractive Genomic Approach

Isolation and structural analysis of phosphorylated oligosaccharides obtained from Escherichia coli J‐5 lipopolysaccharide

Convenient Synthesis of 1,4-Dideoxy-1,4-imino-D-ribitol from D-Ribose

Contact Info

Product

Resources

About