Synthesis of analogues of the O-β-d-Ribofuranosyl nucleoside moiety of liposidomycins. Part 2: role of the hydroxyl groups upon the inhibition of MraY

Dini, C.; Drochon, N.; Guillot, J. C.; Mauvais, Pascale; Walter, P.; Aszodi, J.

doi:10.1016/s0960-894x(00)00714-9

Cited by 54 publications

(32 citation statements)

References 9 publications

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“…Mureidomycin B was a gift from Hoechst (Frankfurt, Germany). The synthesis of the riburamycin analogues has already been described (13)(14)(15)(16).…”

Section: Methodsmentioning

confidence: 99%

Fluorescence Detection-Based Functional Assay for High-Throughput Screening for MraY

Stachyra¹,

Dini²,

Ferrari³

et al. 2004

Antimicrob Agents Chemother

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We have developed a novel assay specific to MraY, which catalyzes the first membrane step in the biosynthesis of bacterial cell wall peptidoglycan. This was accomplished by using UDP-MurNAc-N -dansylpentapeptide, a fluorescent derivative of the MraY nucleotide substrate, and a partially purified preparation of MraY solubilized from membranes of an Escherichia coli overproducing strain. Two versions of the assay were developed, one consisting of the high-pressure liquid chromatography separation of the substrate and product (dansylated lipid I) and the other, without separation and adapted to the high-throughput format, taking advantage of the different fluorescence properties of the nucleotide and lipid I in the reaction medium. The latter assay was validated with a set of natural and synthetic MraY inhibitors.The biosynthesis of bacterial peptidoglycan is a complex two-stage process. The first stage consists in the formation of the monomer unit GlcNAc-MurNAc-(pentapeptide), whereas the second one concerns polymerization and maturation reactions (28). In the first stage, two enzymes, MraY and MurG, have in common their attachment to the cytoplasmic membrane and their processing of lipid intermediates: MraY transfers the phospho-MurNAc-pentapeptide motif onto lipid carrier undecaprenyl phosphate, yielding MurNAc-(pentapeptide)-pyrophosphoryl undecaprenol (lipid I), and MurG then adds the GlcNAc residue to yield GlcNAc-MurNAc-(pentapeptide)-pyrophosphoryl undecaprenol (lipid II), which contains the whole monomer unit. In the present study, we have focused our attention to the MraY transferase, which is an integral membrane protein with ten transmembrane segments, five cytoplasmic domains, and six periplasmic domains including the N-and C-terminal ends (4). Besides the synthesis of lipid I, which is fully reversible, MraY catalyzes in vitro an exchange reaction between UMP and UDP-MurNAc-pentapeptide (23). Owing to its exclusive presence in bacteria and to its essential character, which was demonstrated in Escherichia coli (5), MraY is a target of interest for the discovery of novel antibacterial agents. It is inhibited by non-clinically used antibiotics such as tunicamycin, amphomycin, mureidomycin, liposidomycin, and muraymycins (7,9,22). Recently, simplified analogues of liposidomycin, named riburamycins, have been shown to be powerful MraY inhibitors and to possess antibacterial activities against gram-positive organisms (13-16) (J. Biton, K. Braham, C. Dini, O. Krebs, P. Lassaigne, F. Monti, T. Stachyra, V. Steier, and J. Zhang, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-361, 2002). To date, several specific assays for the MraY activity have been published (6,17,18,27,29,30); however, very few can be adapted to the high-throughput format. In the present work, we took advantage of the fluorescent properties of UDP-MurNAc-N ε -dansylpentapeptide and dansylated lipid I (6, 29) to set up a high-throughput screen (HTS) assay for MraY, which was validated with a set of natural and synthetic ...

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“…Mureidomycin B was a gift from Hoechst (Frankfurt, Germany). The synthesis of the riburamycin analogues has already been described (13)(14)(15)(16).…”

Section: Methodsmentioning

confidence: 99%

Fluorescence Detection-Based Functional Assay for High-Throughput Screening for MraY

Stachyra¹,

Dini²,

Ferrari³

et al. 2004

Antimicrob Agents Chemother

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“…Recent investigations indicate that the 3Љ-OH group (12), the amino group of the aminoribosyl-glycyluridine, and an intact uracil moiety (13) are essential for the inhibition of the Escherichia coli translocase I MraY. The chemical synthesis of the (ϩ)-caprazol (5) was recently accomplished (14), however, this compound only shows weak antibacterial activity.…”

mentioning

confidence: 99%

Identification and Manipulation of the Caprazamycin Gene Cluster Lead to New Simplified Liponucleoside Antibiotics and Give Insights into the Biosynthetic Pathway

Kaysser

Lutsch

Siebenberg

et al. 2009

Journal of Biological Chemistry

127

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“…However, they showed no antibacterial activity when they were subjected to a range of Gram-positive bacteria up to 64 µg/mL (Table 1). Previous studies by us, 33,34,[45][46][47][48][49] and others [50][51][52][53] associated with antibacterial nucleoside natural products indicated that the aminoribosyluridine moiety is the essential structural feature that interacts with the active site of the MraY enzyme. That the lipophilic side chain is not essential for MraY inhibition but rather for antibacterial activity clearly indicates that the side chain contributes to the membrane-permeability of the molecule because MraY is an integral membrane protein and its active site exists on the cytoplasmic side of the membrane.…”

Section: Medicinal Chemistry Of Muraymycinsmentioning

confidence: 96%

Synthesis and Medicinal Chemistry of Muraymycins, Nucleoside Antibiotics

Katsuyama

Ichikawa

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Muraymycins, isolated from a culture broth of Streptomyces sp., are members of a class of naturally occurring nucleoside antibiotics. They are strong inhibitors of the phospho-MurNAc-pentapeptide translocase (MraY), which is responsible for the peptidoglycan biosynthesis. Since MraY is an essential enzyme among bacteria, muraymycins are expected to be a novel antibacterial agent. In this review, our efforts to synthesize muraymycin D2, simplify the chemical structure, improve antibacterial spectrum, and solve the X-ray crystal structure of the muraymycin D2/MraY complex are described.

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Synthesis of analogues of the O-β-d-Ribofuranosyl nucleoside moiety of liposidomycins. Part 2: role of the hydroxyl groups upon the inhibition of MraY

Cited by 54 publications

References 9 publications

Fluorescence Detection-Based Functional Assay for High-Throughput Screening for MraY

Fluorescence Detection-Based Functional Assay for High-Throughput Screening for MraY

Identification and Manipulation of the Caprazamycin Gene Cluster Lead to New Simplified Liponucleoside Antibiotics and Give Insights into the Biosynthetic Pathway

Synthesis and Medicinal Chemistry of Muraymycins, Nucleoside Antibiotics

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