References of "Terrak, Mohammed"
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See detailβ‐Lactam Antibiotics
Terrak, Mohammed ULiege; Frère, Jean-Marie ULiege

in Offermanns, S.; Rosenthal, W. (Eds.) Encyclopedia of Molecular Pharmacology (in press)

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See detailSqualamine and Aminosterol Mimics Inhibit the Peptidoglycan Glycosyltransferase Activity of PBP1b
Boes, Adrien ULiege; Brunel, Jean Michel; Derouaux, Adeline et al

in Antibiotics (2020)

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See detailFluorescence anisotropy assays for high throughput screening of compounds binding to lipid II, PBP1b, FtsW and MurJ.
Boes, Adrien ULiege; Olatunji, Samir; Mohammadi, Tamimount et al

in Scientific Reports (2020), 10(1), 6280

Lipid II precursor and its processing by a flippase and peptidoglycan polymerases are considered key hot spot targets for antibiotics. We have developed a fluorescent anisotropy (FA) assay using a unique ... [more ▼]

Lipid II precursor and its processing by a flippase and peptidoglycan polymerases are considered key hot spot targets for antibiotics. We have developed a fluorescent anisotropy (FA) assay using a unique and versatile probe (fluorescent lipid II) and monitored direct binding between lipid II and interacting proteins (PBP1b, FtsW and MurJ), as well as between lipid II and interacting antibiotics (vancomycin, nisin, ramoplanin and a small molecule). Competition experiments performed using unlabelled lipid II, four lipid II-binding antibiotics and moenomycin demonstrate that the assay can detect compounds interacting with lipid II or the proteins. These results provide a proof-of-concept for the use of this assay in a high-throughput screening of compounds against all these targets. In addition, the assay constitutes a powerful tool in the study of the mode of action of compounds that interfere with these processes. Interestingly, FA assay with lipid II probe has the advantage over moenomycin based probe to potentially identify compounds that interfere with both donor and acceptor sites of the aPBPs GTase as well as compounds that bind to lipid II. In addition, this assay would allow the screening of compounds against SEDS proteins and MurJ which do not interact with moenomycin. [less ▲]

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See detailBiochemical and structural insights into the interaction of the essential domain of FtsN with PBP1b
Boes, Adrien ULiege; Terrak, Mohammed ULiege; Kerff, Frédéric ULiege et al

Poster (2019, November 15)

The mutation W83L within eFtsN reduced binding of FtsN to PBP1b and the activation of PBP1b Evidence for the interaction between PBP1b and eFtsN was shown using different techniques including FP binding ... [more ▼]

The mutation W83L within eFtsN reduced binding of FtsN to PBP1b and the activation of PBP1b Evidence for the interaction between PBP1b and eFtsN was shown using different techniques including FP binding assay, activity assay, cross-linking and x-ray crystallography. eFtsN is sufficient for the specific activation of PBP1b. These results demonstrate that PBP1b is a target of eFtsN and suggest that the direct interaction between eFtsN and PBP1b is the trigger of septal PG synthesis and cell constriction in E. coli. [less ▲]

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See detailRegulation of the peptidoglycan synthases PBPs within the divisome
Terrak, Mohammed ULiege

Conference (2019, June 11)

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See detailRegulation of the Peptidoglycan Polymerase Activity of PBP1b by Antagonist Actions of the Core Divisome Proteins FtsBLQ and FtsN
Boes, Adrien ULiege; olatunji, Samir; Breukink, Eefjan et al

in MBio (2019), 10

Bacterial cell division is governed by a multiprotein complex called divisome, which facilitates a precise cell wall synthesis at midcell and daughter cell separation. Protein-protein interactions and ... [more ▼]

Bacterial cell division is governed by a multiprotein complex called divisome, which facilitates a precise cell wall synthesis at midcell and daughter cell separation. Protein-protein interactions and activity studies using different combinations of the septum synthesis core of the divisome revealed that the glycosyltransferase activity of PBP1b is repressed by FtsBLQ and that the presence of FtsN or LpoB suppresses this inhibition. Moreover, FtsBLQ also inhibits the PBP3 activity on a thioester substrate. These results provide enzymatic evidence of the regulation of the peptidoglycan synthase PBP1b and PBP3 within the divisome. The results confirm that PBP1b plays an important role in E. coli cell division and shed light on the specific role of FtsN, which functions to relieve the repression on PBP1b by FtsBLQ and to initiate septal peptidoglycan synthesis. [less ▲]

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See detailPeptidoglycan glycosyltransferase-ligand binding assay based on tryptophan fluorescence quenching.
Dahmane, Ismahene ULiege; Montagner, Caroline ULiege; Matagne, André ULiege et al

in Biochimie (2018)

Peptidoglycan glycosyltransferases (GTase) of family 51 are essential enzymes for the synthesis of the glycan chains of the bacterial cell wall. They are considered potential antibacterial target, but ... [more ▼]

Peptidoglycan glycosyltransferases (GTase) of family 51 are essential enzymes for the synthesis of the glycan chains of the bacterial cell wall. They are considered potential antibacterial target, but discovery of inhibitors was hampered so far by the lack of efficient and affordable screening assay. Here we used Staphylococcus aureus MtgA to introduce a single tryptophan reporter residue in selected positions flanking the substrates binding cavity of the protein. We selected a mutant (Y181W) that shows strong fluorescence quenching in the presence of moenomycin A and two lipid II analogs inhibitors. The assay provides a simple method to study GTase-ligand interactions and can be used as primary high throughput screening of GTase inhibitors without the need for lipid II substrate or reporter ligands. [less ▲]

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See detailInterplay between Penicillin-binding proteins and SEDS proteins promotes bacterial cell wall synthesis.
Leclercq, Sophie ULiege; Derouaux, Adeline ULiege; Olatunji, Samir ULiege et al

in Scientific Reports (2017), 7

Bacteria utilize specialized multi-protein machineries to synthesize the essential peptidoglycan (PG) cell wall during growth and division. The divisome controls septal PG synthesis and separation of ... [more ▼]

Bacteria utilize specialized multi-protein machineries to synthesize the essential peptidoglycan (PG) cell wall during growth and division. The divisome controls septal PG synthesis and separation of daughter cells. In E. coli, the lipid II transporter candidate FtsW is thought to work in concert with the PG synthases penicillin-binding proteins PBP3 and PBP1b. Yet, the exact molecular mechanisms of their function in complexes are largely unknown. We show that FtsW interacts with PBP1b and lipid II and that PBP1b, FtsW and PBP3 co-purify suggesting that they form a trimeric complex. We also show that the large loop between transmembrane helices 7 and 8 of FtsW is important for the interaction with PBP3. Moreover, we found that FtsW, but not the other flippase candidate MurJ, impairs lipid II polymerization and peptide cross-linking activities of PBP1b, and that PBP3 relieves these inhibitory effects. All together the results suggest that FtsW interacts with lipid II preventing its polymerization by PBP1b unless PBP3 is also present, indicating that PBP3 facilitates lipid II release and/or its transfer to PBP1b after transport across the cytoplasmic membrane. This tight regulatory mechanism is consistent with the cell's need to ensure appropriate use of the limited pool of lipid II. [less ▲]

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See detailElectron paramagnetic resonance and fluorescence studies on potential anticancer properties of two Ru(II) complexes
Collienne, Simon ULiege; Mouithys-Mickalad, Ange ULiege; Terrak, Mohammed ULiege et al

Poster (2016, May 20)

The anti oxydant properties of Ru complexes were determined by EPR.

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See detailGlycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials.
Sauvage, Eric ULiege; Terrak, Mohammed ULiege

in Antibiotics (2016), 5(1),

Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding ... [more ▼]

Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. Although good progress has been made in terms of the functional and structural understanding of GT, finding a clinically useful antibiotic against them has been challenging until now. In contrast, the TP/PBP module has been successfully targeted by beta-lactam derivatives, but the extensive use of these antibiotics has selected resistant bacterial strains that employ a wide variety of mechanisms to escape the lethal action of these antibiotics. In addition to traditional beta-lactams, other classes of molecules (non-beta-lactams) that inhibit PBPs are now emerging, opening new perspectives for tackling the resistance problem while taking advantage of these valuable targets, for which a wealth of structural and functional knowledge has been accumulated. The overall evidence shows that PBPs are part of multiprotein machineries whose activities are modulated by cofactors. Perturbation of these systems could lead to lethal effects. Developing screening strategies to take advantage of these mechanisms could lead to new inhibitors of PG assembly. In this paper, we present a general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes. [less ▲]

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See detailStructure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase.
Sosic, Izidor; Anderluh, Marko; Sova, Matej et al

in Journal of Medicinal Chemistry (2015)

Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin ... [more ▼]

Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions. [less ▲]

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See detailElectron paramagnetic resonance and fluorescence studies on potential anticancer properties of two new Ru(II) complexes : preliminary results
Collienne, Simon ULiege; Terrak, Mohammed ULiege; Mouithys-Mickalad, Ange ULiege et al

Poster (2015, May 22)

Fight against cancer is a priority of today’s research. Since the discovery of the anticancer properties of cisplatin (CisPt) in 1965 by Rosenberg [1], the treatment of cancer by chemotherapy has known ... [more ▼]

Fight against cancer is a priority of today’s research. Since the discovery of the anticancer properties of cisplatin (CisPt) in 1965 by Rosenberg [1], the treatment of cancer by chemotherapy has known great improvements. Unfortunately, CisPt has several side effects and is not effective against all kinds of cancer. Nevertheless its use highlights the great potential of organometallic compounds in the treatment of cancer [2]. Here we investigated the potential anticancer properties of two new organometallic compounds based on ruthenium II : [RuCl(p-cymene)(S2C.IDip)]+(PF6)- and [RuCl(p-cymene)(S2C.ICy)]+(PF6)-, named as LDO436 and LDO437 respectively. [less ▲]

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See detailPositive cooperativity between acceptor and donor sites of the peptidoglycan glycosyltransferase.
Bury, Daniel; Dahmane, Ismahene ULiege; Derouaux, Adeline ULiege et al

in Biochemical Pharmacology (2015), 93(2), 141-50

The glycosyltransferases of family 51 (GT51) catalyze the polymerization of lipid II to form linear glycan chains, which, after cross linking by the transpeptidases, form the net-like peptidoglycan ... [more ▼]

The glycosyltransferases of family 51 (GT51) catalyze the polymerization of lipid II to form linear glycan chains, which, after cross linking by the transpeptidases, form the net-like peptidoglycan macromolecule. The essential function of the GT makes it an attractive antimicrobial target; therefore a better understanding of its function and its mechanism of interaction with substrates could help in the design and the development of new antibiotics. In this work, we have used a surface plasmon resonance Biacore((R)) biosensor, based on an amine derivative of moenomycin A immobilized on a sensor chip surface, to investigate the mechanism of binding of substrate analogous inhibitors to the GT. Addition of increasing concentrations of moenomycin A to the Staphylococcus aureus MtgA led to reduced binding of the protein to the sensor chip as expected. Remarkably, in the presence of low concentrations of the most active disaccharide inhibitors, binding of MtgA to immobilized moenomycin A was found to increase; in contrast competition with moenomycin A occurred only at high concentrations. This finding suggests that at low concentrations, the lipid II analogs bind to the acceptor site and induce a cooperative binding of moenomycin A to the donor site. Our results constitute the first indication of the existence of a positive cooperativity between the acceptor and the donor sites of peptidoglycan GTs. In addition, our study indicates that a modification of two residues (L119N and F120S) within the hydrophobic region of MtgA can yield monodisperse forms of the protein with apparently no change in its secondary structure content, but this is at the expense of the enzyme function. [less ▲]

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See detailBacterial cell wall growth, shape and division.
Derouaux, Adeline ULiege; Terrak, Mohammed ULiege; Den Blaauwen, Tanneke et al

in Bacterial Membranes: Structural and Molecular Biology (2014)

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See detailThe crystal structure of the cell division amidase AmiC reveals the fold of the AMIN domain, a new peptidoglycan binding domain.
Rocaboy, Mathieu; Herman, Raphaël ULiege; Sauvage, Eric ULiege et al

in Molecular Microbiology (2013)

Binary fission is the ultimate step of the prokaryotic cell cycle. In Gram-negative bacteria like Escherichia coli, this step implies the invagination of three biological layers (cytoplasmic membrane ... [more ▼]

Binary fission is the ultimate step of the prokaryotic cell cycle. In Gram-negative bacteria like Escherichia coli, this step implies the invagination of three biological layers (cytoplasmic membrane, peptidoglycan and outer membrane), biosynthesis of the new poles and eventually, daughter cells separation. The latter requires the coordinated action of the N-acetylmuramyl-L-alanine amidases AmiA/B/C and their LytM activators EnvC and NlpD to cleave the septal peptidoglycan. We present here the 2.5 A crystal structure of AmiC which includes the first report of an AMIN domain structure, a beta-sandwich of two symmetrical four-stranded beta-sheets exposing highly conserved motifs on the two outer faces. We show that this N-terminal domain, involved in the localization of AmiC at the division site, is a new peptidoglycan-binding domain. The C-terminal catalytic domain shows an auto-inhibitory alpha helix obstructing the active site. AmiC lacking this helix exhibits by itself an activity comparable to that of the wild type AmiC activated by NlpD. We also demonstrate the interaction between AmiC and NlpD by microscale thermophoresis and confirm the importance of the active site blocking alpha helix in the regulation of the amidase activity. [less ▲]

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