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See detailStructural basis of the inhibition of class A beta-lactamases and penicillin-binding proteins by 6-beta-iodopenicillanate
Sauvage, Eric ULg; Zervosen, Astrid ULg; Dive, Georges ULg et al

in Journal of the American Chemical Society (2009), 131(42), 15262-15269

6-Beta-halogenopenicillanates are powerful, irreversible inhibitors of various beta-lactamases and penicillin-binding proteins. Upon acylation of these enzymes, the inhibitors are thought to undergo a ... [more ▼]

6-Beta-halogenopenicillanates are powerful, irreversible inhibitors of various beta-lactamases and penicillin-binding proteins. Upon acylation of these enzymes, the inhibitors are thought to undergo a structural rearrangement associated with the departure of the iodide and formation of a dihydrothiazine ring, but, to date, no structural evidence has proven this. 6-Beta-iodopenicillanic acid (BIP) is shown here to be an active antibiotic against various bacterial strains and an effective inhibitor of the class A beta-lactamase of Bacillus subtilis BS3 (BS3) and the D,D-peptidase of Actinomadura R39 (R39). Crystals of BS3 and of R39 were soaked with a solution of BIP and their structures solved at 1.65 and 2.2 A, respectively. The beta-lactam and the thiazolidine rings of BIP are indeed found to be fused into a dihydrothiazine ring that can adopt two stable conformations at these active sites. The rearranged BIP is observed in one conformation in the BS3 active site and in two monomers of the asymmetric unit of R39, and is observed in the other conformation in the other two monomers of the asymmetric unit of R39. The BS3 structure reveals a new mode of carboxylate interaction with a class A beta-lactamase active site that should be of interest in future inhibitor design. [less ▲]

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See detailBacillus amyloliquefaciens GA1 as a source of potent antibiotics and other secondary metabolites for biocontrol of plant pathogens.
Arguelles-Arias, A.; Ongena, MARC ULg; Halimi, B. et al

in Microbial Cell Factories (2009), 8(1), 63

ABSTRACT: BACKGROUND: Phytopathogenic fungi affecting crop and post-harvested vegetables are a major threat to food production and food storage. To face these drawbacks, producers have become increasingly ... [more ▼]

ABSTRACT: BACKGROUND: Phytopathogenic fungi affecting crop and post-harvested vegetables are a major threat to food production and food storage. To face these drawbacks, producers have become increasingly dependent on agrochemicals. However, intensive use of these compounds has led to the emergence of pathogen resistance and severe negative environmental impacts. There are also a number of plant diseases for which chemical solutions are ineffective or non-existent as well as an increasing demand by consumers for pesticide-free food. Thus, biological control through the use of natural antagonistic microorganisms has emerged as a promising alternative to chemical pesticides for more rational and safe crop management. RESULTS: The genome of the plant-associated B. amyloliquefaciens GA1 was sample sequenced. Several gene clusters involved in the synthesis of biocontrol agents were detected. Four gene clusters were shown to direct the synthesis of the cyclic lipopeptides surfactin, iturin A and fengycin as well as the iron-siderophore bacillibactin. Beside these non-ribosomaly synthetised peptides, three additional gene clusters directing the synthesis of the antibacterial polyketides macrolactin, bacillaene and difficidin were identified. Mass spectrometry analysis of culture supernatants led to the identification of these secondary metabolites, hence demonstrating that the corresponding biosynthetic gene clusters are functional in strain GA1. In addition, genes encoding enzymes involved in synthesis and export of the dipeptide antibiotic bacilysin were highlighted. However, only its chlorinated derivative, chlorotetaine, could be detected in culture supernatants. On the contrary, genes involved in ribosome-dependent synthesis of bacteriocin and other antibiotic peptides were not detected as compared to the reference strain B. amyloliquefaciens FZB42. CONCLUSION: The production of all of these antibiotic compounds highlights B. amyloliquefaciens GA1 as a good candidate for the development of biocontrol agents. [less ▲]

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See detailSubstrate-induced inactivation of the Escherichia coli AmiD N-acetylmuramoyl-L-alanine amidase highlights a new strategy to inhibit this class of enzyme.
Pennartz, Anne; Genereux, Catherine ULg; Parquet, Claudine et al

in Antimicrobial Agents and Chemotherapy (2009), 53(7), 2991-7

In the eubacterial cell, the peptidoglycan is perpetually hydrolyzed throughout the cell cycle by different enzymes such as lytic transglycosylases, endopeptidases, and amidases. In Escherichia coli, four ... [more ▼]

In the eubacterial cell, the peptidoglycan is perpetually hydrolyzed throughout the cell cycle by different enzymes such as lytic transglycosylases, endopeptidases, and amidases. In Escherichia coli, four N-acetylmuramoyl-l-alanine amidases, AmiA, -B, -C, and -D, are present in the periplasm. AmiA, -B, and -C are soluble enzymes, whereas AmiD is a lipoprotein anchored in the outer membrane. To determine more precisely the specificity and the kinetic parameters of AmiD, we overproduced and purified the native His-tagged AmiD in the presence of detergent and a soluble truncated form of this enzyme by removing its signal peptide and the cysteine residue responsible for its lipidic anchorage. AmiD is a zinc metalloenzyme and is inactivated by a metal chelator such as EDTA. Native His-tagged and truncated AmiD hydrolyzes peptidoglycan fragments that have at least three amino acids in their peptide chains, and the presence of an anhydro function on the N-acetylmuramic acid is not essential for its activity. The soluble truncated AmiD exhibits a biphasic kinetic time course that can be explained by the inactivation of the enzyme by the substrate. This behavior highlights a new strategy to inhibit this class of enzymes. [less ▲]

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See detailActivities of ceftobiprole and other cephalosporins against extracellular and intracellular (THP-1 macrophages and keratinocytes) forms of methicillin-susceptible and methicillin-resistant Staphylococcus aureus.
Lemaire, Sandrine; Glupczynski, Youri; Duval, Valerie et al

in Antimicrobial Agents and Chemotherapy (2009), 53(6), 2289-97

Staphylococcus aureus is an opportunistic intracellular organism. Although they poorly accumulate in eukaryotic cells, beta-lactams show activity against intracellular methicillin (methicillin ... [more ▼]

Staphylococcus aureus is an opportunistic intracellular organism. Although they poorly accumulate in eukaryotic cells, beta-lactams show activity against intracellular methicillin (methicillin)-susceptible S. aureus (MSSA) if the exposure times and the drug concentrations are sufficient. Intraphagocytic methicillin-resistant S. aureus (MRSA) strains are susceptible to penicillins and carbapenems because the acidic pH favors the acylation of PBP 2a by these beta-lactams through pH-induced conformational changes. The intracellular activity (THP-1 macrophages and keratinocytes) of ceftobiprole, which shows almost similar in vitro activities against MRSA and MSSA in broth, was examined against a panel of hospital-acquired and community-acquired MRSA strains (MICs, 0.5 to 2.0 mg/liter at pH 7.4 and 0.25 to 1.0 mg/liter at pH 5.5) and was compared with its activity against MSSA isolates. The key pharmacological descriptors {relative maximal efficacy (E(max)), relative potency (the concentration causing a reduction of the inoculum halfway between E(0) and E(max) [EC(50)]), and static concentration (C(s))} were measured. All strains showed sigmoidal dose-responses, with E(max) being about a 1 log(10) CFU decrease from the postphagocytosis inoculum, and EC(50) and C(s) being 0.2 to 0.3x and 0.6 to 0.9x the MIC, respectively. Ceftobiprole effectively competed with Bocillin FL (a fluorescent derivative of penicillin V) for binding to PBP 2a at both pH 5.5 and pH 7.4. In contrast, cephalexin, cefuroxime, cefoxitin, or ceftriaxone (i) were less potent in PBP 2a competitive binding assays, (ii) showed only partial restoration of the activity against MRSA in broth at acidic pH, and (iii) were collectively less effective against MRSA in THP-1 macrophages and were ineffective in keratinocytes. The improved activity of ceftobiprole toward intracellular MRSA compared with the activities of conventional cephalosporins can be explained, at least in part, by its greater ability to bind to PBP 2a not only at neutral but also at acidic pH. [less ▲]

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See detailBacillus lipopeptides properties leading to versatile weapons for plant disease biocontrol
Leclere, V.; Bechet, M.; Brans, Alain ULg et al

Conference (2008, March)

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See detailThe Chitobiose-Binding Protein, DasA, Acts as a Link between Chitin Utilization and Morphogenesis in Streptomyces Coelicolor
Colson, Séverine ULg; van Wezel, G. P.; Craig, Matthias ULg et al

in Microbiology (2008), 154(Pt 2), 373-82

Streptomycetes are mycelial soil bacteria that undergo a developmental programme that leads to sporulating aerial hyphae. As soil-dwelling bacteria, streptomycetes rely primarily on natural polymers such ... [more ▼]

Streptomycetes are mycelial soil bacteria that undergo a developmental programme that leads to sporulating aerial hyphae. As soil-dwelling bacteria, streptomycetes rely primarily on natural polymers such as cellulose, xylan and chitin for the colonization of their environmental niche and therefore these polysaccharides may play a critical role in monitoring the global nutritional status of the environment. In this work we analysed the role of DasA, the sugar-binding component of the chitobiose ATP-binding cassette transport system, in informing the cell of environmental conditions, and its role in the onset of development and in ensuring correct sporulation. The chromosomal interruption of dasA resulted in a carbon-source-dependent vegetative arrest phenotype, and we identified a second DasR-dependent sugar transporter, in addition to the N-acetylglucosamine phosphotransferase system (PTS(GlcNAc)), that relates primary metabolism to development. Under conditions that allowed sporulation, highly aberrant spores with many prematurely produced germ tubes were observed. While GlcNAc locks streptomycetes in the vegetative state, a high extracellular concentration of the GlcNAc polymer chitin has no effect on development. The striking distinction is due to a difference in the transporters responsible for the import of GlcNAc, which enters via the PTS, and of chitin, which enters as the hydrolytic product chitobiose (GlcNAc(2)) through the DasABC transporter. A model explaining the role of these two essentially different transport systems in the control of development is provided. [less ▲]

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See detailTemperature dependence of mycosubtilin homologue production in Bacillus subtilis ATCC6633.
Fickers, Patrick ULg; Leclere, Valerie; Guez, Jean*-Sebastien et al

in Research in Microbiology (2008), 159(6), 449-57

Bacillus subtilis ATCC6633 produces mycosubtilin, a non-ribosomally synthesized lipopeptide of the iturin family which presents antagonistic activities toward various phytopathogens. Different homologues ... [more ▼]

Bacillus subtilis ATCC6633 produces mycosubtilin, a non-ribosomally synthesized lipopeptide of the iturin family which presents antagonistic activities toward various phytopathogens. Different homologues with fatty acid moiety varying from C15 to C17 are usually co-produced, with their biological activities increasing with the number of carbons in the fatty acid chain. In the present report, we highlight that growth temperature modulates both the extent of mycosubtilin production and the relative abundance of the different homologues. A 30-fold increase in mycosubtilin production was observed when the temperature was decreased from 37 degrees C to 25 degrees C for both strain ATCC6633 and its derivative BBG100, a constitutive mycosubtilin overproducer. However, no significant difference in either the expression of the mycosubtilin synthetase encoding genes or in the intracellular synthetase concentration could be found, suggesting that the observed phenotype originated from a higher mycosubtilin synthetase turnover at lower temperature. We also point out that lower growth temperature leads to an increased proportion of odd-numbered fatty acid homologues as a consequence of de novo synthesis of C17 anteiso fatty acid following cell adaptation to low temperatures. [less ▲]

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See detailBacterial peptidoglycan (murein) hydrolases.
Vollmer, Waldemar; Joris, Bernard ULg; Charlier, Paulette ULg et al

in FEMS Microbiology Reviews (2008), 32(2), 259-86

Most bacteria have multiple peptidoglycan hydrolases capable of cleaving covalent bonds in peptidoglycan sacculi or its fragments. An overview of the different classes of peptidoglycan hydrolases and ... [more ▼]

Most bacteria have multiple peptidoglycan hydrolases capable of cleaving covalent bonds in peptidoglycan sacculi or its fragments. An overview of the different classes of peptidoglycan hydrolases and their cleavage sites is provided. The physiological functions of these enzymes include the regulation of cell wall growth, the turnover of peptidoglycan during growth, the separation of daughter cells during cell division and autolysis. Specialized hydrolases enlarge the pores in the peptidoglycan for the assembly of large trans-envelope complexes (pili, flagella, secretion systems), or they specifically cleave peptidoglycan during sporulation or spore germination. Moreover, peptidoglycan hydrolases are involved in lysis phenomena such as fratricide or developmental lysis occurring in bacterial populations. We will also review the current view on the regulation of autolysins and on the role of cytoplasm hydrolases in peptidoglycan recycling and induction of beta-lactamase. [less ▲]

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See detailToward the characterization of peptidoglycan structure and protein-peptidoglycan interactions by solid-state NMR spectroscopy.
Kern, Thomas; Hediger, Sabine; Muller, Patrick et al

in Journal of the American Chemical Society (2008), 130(17), 5618-9

Solid-state NMR spectroscopy is applied to intact peptidoglycan sacculi of the Gram-negative bacterium Escherichia coli. High-quality solid-state NMR spectra allow atom-resolved investigation of the ... [more ▼]

Solid-state NMR spectroscopy is applied to intact peptidoglycan sacculi of the Gram-negative bacterium Escherichia coli. High-quality solid-state NMR spectra allow atom-resolved investigation of the peptidoglycan structure and dynamics as well as the study of protein-peptidoglycan interactions. [less ▲]

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See detailCrystal structure and activity of Bacillus subtilis YoaJ (EXLX1), a bacterial expansin that promotes root colonization.
Kerff, Frédéric ULg; Amoroso, Ana Maria ULg; Herman, Raphaël ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2008), 105(44), 16876-81

We solved the crystal structure of a secreted protein, EXLX1, encoded by the yoaJ gene of Bacillus subtilis. Its structure is remarkably similar to that of plant beta-expansins (group 1 grass pollen ... [more ▼]

We solved the crystal structure of a secreted protein, EXLX1, encoded by the yoaJ gene of Bacillus subtilis. Its structure is remarkably similar to that of plant beta-expansins (group 1 grass pollen allergens), consisting of 2 tightly packed domains (D1, D2) with a potential polysaccharide-binding surface spanning the 2 domains. Domain D1 has a double-psi beta-barrel fold with partial conservation of the catalytic site found in family 45 glycosyl hydrolases and in the MltA family of lytic transglycosylases. Domain D2 has an Ig-like fold similar to group 2/3 grass pollen allergens, with structural features similar to a type A carbohydrate-binding domain. EXLX1 bound to plant cell walls, cellulose, and peptidoglycan, but it lacked lytic activity against a variety of plant cell wall polysaccharides and peptidoglycan. EXLX1 promoted plant cell wall extension similar to, but 10 times weaker than, plant beta-expansins, which synergistically enhanced EXLX1 activity. Deletion of the gene encoding EXLX1 did not affect growth or peptidoglycan composition of B. subtilis in liquid medium, but slowed lysis upon osmotic shock and greatly reduced the ability of the bacterium to colonize maize roots. The presence of EXLX1 homologs in a small but diverse set of plant pathogens further supports a role in plant-bacterial interactions. Because plant expansins have proved difficult to express in active form in heterologous systems, the discovery of a bacterial homolog opens the door for detailed structural studies of expansin function. [less ▲]

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See detailStructural and mechanistic basis of penicillin-binding protein inhibition by lactivicins
Macheboeuf, Pauline; Fischer, Delphine S; Brown, Tom Jr et al

in Nature Chemical Biology (2007), 3(9), 565-569

beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved ... [more ▼]

beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition(1). Lactivicin (LTV; 1) contains separate cycloserine and c-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam(2-4). Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria. [less ▲]

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See detailFunctional characteristics of TauA binding protein from TauABC Escherichia coli system
Javaux, C.; Joris, Bernard ULg; De Witte, P.

in Protein Journal (2007), 26(4), 231-238

Although TauA shares few common characteristics with other known periplasmic binding protein, TauA is a putative periplasmic binding protein, part of tauABCD gene cluster involved in sulfonate transport ... [more ▼]

Although TauA shares few common characteristics with other known periplasmic binding protein, TauA is a putative periplasmic binding protein, part of tauABCD gene cluster involved in sulfonate transport in sulphate starvation condition. This protein was expressed in E. coli BL 21 and purified before to assess its binding functionalities. Measurement of K (d) value (mean 11.3 nM) by binding/dialysis studies revealed high affinity and specificity with taurine and also indicated that TauA possessed a unique binding site for its ligand. Comparisons with other periplasmic binding proteins suggests TauA plays a major role in ABC transport system and could be ideal candidate to serve as taurine catcher in biological fluids. [less ▲]

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See detailPREDetector: A new tool to identify regulatory elements in bacterial genomes
Hiard, Samuel ULg; Marée, Raphaël ULg; Colson, Séverine ULg et al

in Biochemical and Biophysical Research Communications (2007), 357(4), 861-864

In the post-genomic area, the prediction of transcription factor regulons by position weight matrix-based programmes is a powerful approach to decipher biological pathways and to modelize regulatory ... [more ▼]

In the post-genomic area, the prediction of transcription factor regulons by position weight matrix-based programmes is a powerful approach to decipher biological pathways and to modelize regulatory networks in bacteria. The main difficulty once a regulon prediction is available is to estimate its reliability prior to start expensive experimental validations and therefore trying to find a way how to identify true positive hits from an endless list of potential target genes of a regulatory protein. Here we introduce PREDetector (Prokaryotic Regulatory Elements Detector), a tool developed for predicting regulons of DNA-binding proteins in bacterial genomes that, beside the automatic prediction, scoring and positioning of potential binding sites and their respective target genes in annotated bacterial genomes, it also provides an easy way to estimate the thresholds where to find reliable possible new target genes. PREDetector can be downloaded freely at http://www.montefiore.ulg.ac.be/-hiard/PreDetector (c) 2007 Published by Elsevier Inc. [less ▲]

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See detailSynthesis of anhydro-muramic acid derivatives as substrates for MurNAc amidase
Mercier, Frédéric; Zervosen, Astrid ULg; Lemaire, Christian ULg et al

Poster (2007, March 22)

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See detail1H, 13C and 15N resonance assignments of YajG, an Escherichia coli protein of unknown structure and function.
Boudet, Julien; Chouquet, Anne; Chahboune, Aicha et al

in Biomolecular NMR assignments (2007), 1(1), 89-91

The ampG gene codes for a permease required to uptake anhydro-muropeptides into bacterial cytoplasm. Located upstream in the same operon, is another 579-base-pair-long open reading frame encoding a ... [more ▼]

The ampG gene codes for a permease required to uptake anhydro-muropeptides into bacterial cytoplasm. Located upstream in the same operon, is another 579-base-pair-long open reading frame encoding a putative lipoprotein YajG, whose nearly complete 1H,13C,15N assignments are reported here. [less ▲]

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See detailSurfactin and fengycin lipopeptides of Bacillus subtilis as elicitors of induced systemic resistance in plants
Ongena, MARC ULg; Jourdan, Emmanuel ULg; Adam, Akram ULg et al

in Environmental Microbiology (2007), 9(4), 1084-1090

Multiple strains of Bacillus spp. were demonstrated to stimulate plant defence responses. However, very little is known about the nature of molecular determinants secreted by these Gram-positive bacteria ... [more ▼]

Multiple strains of Bacillus spp. were demonstrated to stimulate plant defence responses. However, very little is known about the nature of molecular determinants secreted by these Gram-positive bacteria that are responsible for the elicitation of the induced systemic resistance (ISR) phenomenon. This study shows that the lipopeptides surfactins and fengycins may be involved in this elicitation process. In bean, pure fengycins and surfactins provided a significant ISR-mediated protective effect on bean plants, similar to the one induced by living cells of the producing strain S499. Moreover, experiments conducted on bean and tomato plants showed that overexpression of both surfactin and fengycin biosynthetic genes in the naturally poor producer Bacillus subtilis strain 168 was associated with a significant increase in the potential of the derivatives to induce resistance. In tomato cells, key enzymes of the lipoxygenase pathway appeared to be activated in resistant plants following induction by lipopeptide overproducers. To our knowledge, such lipopeptides constitute a novel class of compounds from non-pathogenic bacteria that can be perceived by plant cells as signals to initiate defence mechanisms. [less ▲]

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See detailConformational and thermodynamic changes of the repressor/DNA operator complex upon monomerization shed new light an regulation mechanisms of bacterial resistance against beta-lactam antibiotics
Boudet, J.; Duval, V.; Van Melckebeke, H. et al

in Nucleic Acids Research (2007), 35(13), 4384-4395

In absence of beta-lactam antibiotics, Blal and Mecl homodimeric repressors negatively control the expression of genes involved in P-lactam resistance in Bacillus licheniformis and in Staphylococcus ... [more ▼]

In absence of beta-lactam antibiotics, Blal and Mecl homodimeric repressors negatively control the expression of genes involved in P-lactam resistance in Bacillus licheniformis and in Staphylococcus aureus. Subsequently to P-lactam presence, Blal/Mecl is inactivated by a single-point proteolysis that separates its N-terminal DNA-binding domain to its C-terminal domain responsible for its dimerization. Concomitantly to this proteolysis, the truncated repressor acquires a low affinity for its DNA target that explains the expression of the structural gene for resistance. To understand the loss of the high DNA affinity of the truncated repressor, we have determined the different dissociation constants of the system and solved the solution structure of the B. licheniformis monomeric repressor complexed to the semi-operating sequence OP1, of blaP (1/20P(1)blaP) by using a de novo docking approach based on inter-molecular nuclear Overhauser effects and chemical-shift differences measured on each macromolecular partner. Although the N-terminal domain of the repressor is not subject to internal structural rearrangements upon DNA binding, the molecules adopt a tertiary conformation different from the crystallographic operator-repressor dimer complex, leading to a 300 rotation of the monomer with respect to a central axis extended across the DNA. These results open new insights for the repression and induction mechanisms of bacterial resistance to beta-lactams. [less ▲]

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See detailAdsorption Properties of the Penicillin Derivative DTPA on Gold Substrates
Dreesen, Laurent ULg; Silien, Christophe; Volcke, Cédric et al

in Chemphyschem : A European Journal of Chemical Physics and Physical Chemistry (2007), 8(7), 1071-1076

Despite the large number of articles and patents dealing with penicillin and other b-lactam antibiotics, there have been no reports about the self-assembly of such substances as monolayers on gold ... [more ▼]

Despite the large number of articles and patents dealing with penicillin and other b-lactam antibiotics, there have been no reports about the self-assembly of such substances as monolayers on gold surfaces. The main reason stems from the high reactivity of the b-lactam ring, which hinders the development of molecules possessing this entity together with a metal-anchoring function. Herein, we present the synthesis of a novel molecule, 6-[(R,S)-5-(1,2-dithiolan-3-yl)pentanoyl-amino]-penicillanic acid, which combines the b-lactam ring and a metal-anchoring group. Using spectroscopic tools, we demonstrate the chemisorption of this compound on gold as self-assembled monolayers without any alteration of the penicillin pharmacophore and document its reactivity towards a penicillin-binding protein, BlaR-CTD. Our work is a preliminary step towards the development of new biosensors and well-ordered protein arrays, both based on the high affinity of penicillin for penicillin-binding proteins. [less ▲]

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See detailThe sugar phosphotransferase system of Streptomyces coelicolor is regulated by the GntR-family regulator DasR and links N-acetylglucosamine metabolism to the control of development
Rigali, Sébastien ULg; Nothaft, H.; Noens, E. E. E. et al

in Molecular Microbiology (2006), 61(5), 1237-1251

Members of the soil-dwelling, sporulating prokaryotic genus Streptomyces are indispensable for the recycling of the most abundant polysaccharides on earth (cellulose and chitin), and produce a wide range ... [more ▼]

Members of the soil-dwelling, sporulating prokaryotic genus Streptomyces are indispensable for the recycling of the most abundant polysaccharides on earth (cellulose and chitin), and produce a wide range of antibiotics and industrial enzymes. How do these organisms sense the nutritional state of the environment, and what controls the signal for the switch to antibiotic production and morphological development? Here we show that high extracellular concentrations of N-acetylglucosamine, the monomer of chitin, prevent Streptomyces coelicolor progressing beyond the vegetative state, and that this effect is absent in a mutant defective of N-acetylglucosamine transport. We provide evidence that the signal is transmitted through the GntR-family regulator DasR, which controls the N-acetylglucosamine regulon, including the pts genes ptsH, ptsI and crr needed for uptake of N-acetylglucosamine. Deletion of dasR or the pts genes resulted in a bald phenotype. Binding of DasR to its target genes is abolished by glucosamine 6-phosphate, a central molecule in N-acetylglucosamine metabolism. Extracellular complementation experiments with many bld mutants showed that the dasR mutant is arrested at an early stage of the developmental programme, and does not fit in the previously described bld signalling cascade. Thus, for the first time we are able to directly link carbon (and nitrogen) metabolism to development, highlighting a novel type of metabolic regulator, which senses the nutritional state of the habitat, maintaining vegetative growth until changing circumstances trigger the switch to sporulation. Our work, and the model it suggests, provide new leads towards understanding how microorganisms time developmental commitment. [less ▲]

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