Antibacterial agents specifically inhibiting lipopolysaccharide synthesis

Goldman, Robert C.; Kohlbrenner, William E.; Lartey, Paul A.; Pernet, André G.

doi:10.1038/329162a0

Cited by 147 publications

(64 citation statements)

References 15 publications

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“…Several inhibitors of CMP-KDO synthase have been described (147)(148)(149)(150)(151). These have promise as antibacterial agents.…”

Section: Biosynthesis and Activation Of Kdomentioning

confidence: 99%

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Biochemistry Of Endotoxins

Raetz¹

1990

Annual Review of Biochemistry

166

192

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“…Several inhibitors of CMP-KDO synthase have been described (147)(148)(149)(150)(151). These have promise as antibacterial agents.…”

Section: Biosynthesis and Activation Of Kdomentioning

confidence: 99%

“…These have promise as antibacterial agents. One of these compounds ( Figure 9, inset) is a 2,8-dideoxy-8-amino analog of KDO, in which the amino function is acylated with the dipeptide L-Ala-L-Ala (147,148). The latter facilitates the uptake and concentration of the drug via the oligopeptide permease (147,148).…”

Section: Biosynthesis and Activation Of Kdomentioning

confidence: 99%

Biochemistry Of Endotoxins

Raetz¹

1990

Annual Review of Biochemistry

166

192

View full text Add to dashboard Cite

“…This has led several groups to pursue the inhibition of Kdo metabolism as a path towards the discovery of novel anti-infective agents against Gram-negative bacteria (Hammond et al, 1987; Goldman et al, 1987).…”

mentioning

confidence: 99%

Catalytic mechanism of 3‐deoxy‐d‐manno‐2‐octulosonate‐8‐phosphate synthase

Baasov

Sheffer-Dee-Noor

Kohen

et al. 1993

European Journal of Biochemistry

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The proposed mechanistic pathway for the reaction catalyzed by 3-deoxy-D-manno-2-octulosonate-%phosphate (Kdo8P) synthase was examined in terms of the structure of the putative bisphosphate intermediate. Two 2-deoxy analogues of the product Kdo8P, having been structurally prohibited from undergoing the ring-opening and possessing the stereochemistry of either the u-pyronase (compound 1) or the P-pyranose form (compound 2) of the product, were synthesized and probed as inhibitors for the synthase. It was found that both analogues bind to the enzyme and are competitive inhibitors with respect to phosphoenolpyruvate binding, having K , values of 470 pM and 303 pM, respectively. Comparison of this data to the K, value of the tautomeric mixture of the product Kdo8P (K, = 590 pM) suggests that both the (x-and the /I-pyranose anomers (65.8% and 3.1%, respectively at neutral pH) bind to the enzyme with a slight (1.13 kJ/mol) preference for the p-anomer, and that the C2 hydroxyl does not contribute to the binding. This uncertain stereochemical preference exhibited by the enzyme for the stereoisomers at the anomeric carbon suggests that the carboxylate binding site of the product is indistinct, while the hydroxyl and carboxylate binding sites may be interchangeable. More importantly, however, the isosteric phosphonate analogue 2,6-anhydro-3-deoxy-2~-phosphonylmethyl-8-phosphate-~-glycero-~-tulo-octonate (3), which mimics the topological and electrostatic properties of the proposed cyclic intermediate, was found to be the most potent inhibitor of the enzyme with a K, value of 5 pM. Two hitherto unrecognized aspects of the mechanism of the synthase were identified. First, the results showing that the cyclic analogues 1, 2 and 3 are inhibitors of the enzyme whereas the previously reported acyclic analogue, which contains no carbonyl group at C2 and may thus resemble the open-chain form of Kdo8P, is not an inhibitor, suggest that the pyranose form and not the open-chain acyclic form of the putative bisphosphate intermediate is handled by the enzyme. Second, since the overall stereochemical course of the transformation mediated by the synthase has been shown to involve si face addition of phosphoenolpyruvate to the re face of the carbonyl of arabinose 5-phosphate, the present observation involving analogue 3 suggests that the bisphosphate intermediate formed during the initial steps of synthesis may have the pyranose structure with the anomeric phosphate located in the P-configuration. Enzvmes. 3-Deoxv-~-manno-2-octulosonate-8-uhos~hate svnthase (EC 4.1.2.16); j-enoZpyruvylshikimate-3-phdsphate synthase (EC 2.5.1.19). 3-Deoxy-D-manno-2-octulosonical., 1978). This has led several groups to pursue the inhibition of Kdo metabolism as a path towards the discovery of novel anti-infective agents against Gram-negative bacteria (Hammond et al., 1987;Goldman et al., 1987).There are at least four enzymes involved in the synthesis and utilization of Kdo (Unger, 1981). The actual precursor is its %phosphate (Kdo8P), which is formed by an ...

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“…The antibacterial activity of compound IV is limited to Gram-negative bacteria, and inhibition of LPS synthesis at the level of CMP-KDO synthetase was its mode of action for several species of Gram-negative enteric bacteria (Capobianco et al, 1987;Goldman et al, 1987Goldman et al, , 1988aKadam et al, 1989). Inhibition of LPS synthesis caused accumulation of both direct precursor to LPS as well as lipid-A-related byproducts, and halted growth.…”

Section: Mode Of Action Of Compound IV On a Turnefaciens Biotype I mentioning

confidence: 99%

Inhibition of lipopolysaccharide synthesis in Agrobacterium tumefaciens and Aeromonas salmonicida

Goldman

Capobianco

Doran

et al. 1992

Journal of General Microbiology

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Lipopolysaccharide (LPS) synthesis was inhibited, new lipid A metabolites accumulated, and growth ceased, when the plant pathogen Agrobacterium tumefaciens and the fish pathogen Aeromonas sdmonicida were treated with an antibacterial agent which specifically inhibits CTP:CMP-3-deoxy-manno-octulosonate cytidylyltransferase (CMP-KDO synthase). The new lipid A metabolites were purified by chromatography on DEAE-cellulose and chemically analysed. Metabolites isolated from both bacterial species contained glucosamine and phosphate in a 1 : 1 molar ratio, and 3-OH-C14:0 was the major fatty acid present (1 mol and 1.4 mol per mol glucosamine for A. tumefaciens and A. salmonicida, respectively). Inhibition of LPS synthesis by CMP-KDO synthase inhibitor had no effect on the initial kinetics of A. tumefaciens attachment to cultured carrot cells, but did inhibit cell aggregation normally induced by bacterial cellulose synthesis. Bacteria treated with inhibitor remained viable and able to synthesize protein at 15% the rate of control cells, indicating that the lack of cellulose-induced aggregation was not due to the inability of bacteria to make protein, but rather the inability to respond normally to the bacterialplant cell interaction.

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Antibacterial agents specifically inhibiting lipopolysaccharide synthesis

Cited by 147 publications

References 15 publications

Biochemistry Of Endotoxins

Biochemistry Of Endotoxins

Catalytic mechanism of 3‐deoxy‐d‐manno‐2‐octulosonate‐8‐phosphate synthase

Inhibition of lipopolysaccharide synthesis in Agrobacterium tumefaciens and Aeromonas salmonicida

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