References of "Frère, Jean-Marie"
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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 (2021)

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See detailInteractions between Avibactam and Ceftazidime-Hydrolyzing Class D β-Lactamases
Frère, Jean-Marie ULiege; Bogaerts, P.; Huang, T.-D. et al

in Biomolecules (2020), 10(3),

Class D β-lactamases exhibit very heterogeneous hydrolysis activity spectra against the various types of clinically useful β-lactams. Similarly, and according to the available data, their sensitivities to ... [more ▼]

Class D β-lactamases exhibit very heterogeneous hydrolysis activity spectra against the various types of clinically useful β-lactams. Similarly, and according to the available data, their sensitivities to inactivation by avibactam can vary by a factor of more than 100. In this paper, we performed a detailed kinetic study of the interactions between two ceftazidime-hydrolyzing OXA enzymes and showed that they were significantly more susceptible to avibactam than several other class D enzymes that do not hydrolyze ceftazidime. From a clinical point of view, this result is rather interesting if one considers that avibactam is often administered in combination with ceftazidime. [less ▲]

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See detailA standard numbering scheme for class C β-lactamases
Mack, A. R.; Barnes, M. D.; Taracila, M. A. et al

in Antimicrobial Agents and Chemotherapy (2020), 64(3),

Unlike for classes A and B, a standardized amino acid numbering scheme has not been proposed for the class C (AmpC) β-lactamases, which complicates communication in the field. Here, we propose a scheme ... [more ▼]

Unlike for classes A and B, a standardized amino acid numbering scheme has not been proposed for the class C (AmpC) β-lactamases, which complicates communication in the field. Here, we propose a scheme developed through a collaborative approach that considers both sequence and structure, preserves traditional numbering of catalytically important residues (Ser64, Lys67, Tyr150, and Lys315), is adaptable to new variants or enzymes yet to be discovered and includes a variation for genetic and epidemiological applications. Copyright © 2020 American Society for Microbiology. All Rights Reserved. [less ▲]

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See detail4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-beta-lactamase inhibitors
Gavara, L.; Sevaille, L.; De Luca, F. et al

in European Journal of Medicinal Chemistry (2020), 208

Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors ... [more ▼]

Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the microM to sub-microM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the compound antibacterial activity was limited by poor outer membrane penetration. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several beta-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs. [less ▲]

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See detailFull Pre-Steady-State Kinetic Analysis of Single Nucleotide Incorporation by DNA Polymerases
Renders, M.; Frère, Jean-Marie ULiege; Toye, Dominique ULiege et al

in Current protocols in nucleic acid chemistry (2019), 78(1), 98

By measuring a DNA polymerase incorporation reaction on a very short time scale (5 ms to 10 s) and with a high enzyme concentration, the isolated event of a single nucleotide incorporation can be analyzed ... [more ▼]

By measuring a DNA polymerase incorporation reaction on a very short time scale (5 ms to 10 s) and with a high enzyme concentration, the isolated event of a single nucleotide incorporation can be analyzed. Practically, this is done using a quench-flow instrument, which allows the rapid mixing of the enzyme-primer/template with the nucleotide substrate, after which the reaction is quenched and analyzed. We describe how to titrate the enzyme active site, how to determine, via a scouting experiment, the rate-limiting step in the polymerization reaction, and how to measure the apparent kpol , Kd(DNA) , and Kd(N) using burst or single-turnover experiments. We include equations for the calculation of the processivity of the polymerase, its nucleotide incorporation specificity and preference, and the activation energy difference for the incorporation of an incorrect nucleotide. Data analysis is discussed, as this is an essential part of accurate data generation in kinetic analyses. © 2019 by John Wiley & Sons, Inc. © 2019 John Wiley & Sons, Inc. [less ▲]

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See detailKinetic analysis of N-alkylaryl carboxamide hexitol nucleotides as substrates for evolved polymerases
Renders, M.; Dumbre, S.; Abramov, M. et al

in Nucleic Acids Research (2019), 47(5), 2160-2168

Six 1,5-anhydrohexitol uridine triphosphates were synthesized with aromatic substitutions appended via a carboxamide linker to the 5-position of their bases. An improved method for obtaining such 5 ... [more ▼]

Six 1,5-anhydrohexitol uridine triphosphates were synthesized with aromatic substitutions appended via a carboxamide linker to the 5-position of their bases. An improved method for obtaining such 5-substituted hexitol nucleosides and nucleotides is described. The incorporation profile of the nucleotide analogues into a DNA duplex overhang using recently evolved XNA polymerases is compared. Long, mixed HNA sequences featuring the base modifications are generated. The apparent binding affinity of four of the nucleotides to the enzyme, the rate of the chemical step and of product release, plus the specificity constant for the incorporation of these modified nucleotides into a DNA duplex overhang using the HNA polymerase T6G12 I521L are determined via pre-steady-state kinetics. HNA polymers displaying aromatic functional groups could have significant impact on the isolation of stable and high-affinity binders and catalysts, or on the design of nanomaterials. © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License [less ▲]

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See detailStudy of the outer membrane permeability of Pseudomonas aeruginosa to ß-lactam antibiotics
Amisano, Francesco ULiege; Silvestri, Mauro ULiege; Mercuri, Paola ULiege et al

Poster (2017, June 17)

Background The resistance of Gram negative bacteria toward β-lactam antibiotics is caused by the interplay between four independent factors: i) the alteration of the sensitivity of the target enzymes, the ... [more ▼]

Background The resistance of Gram negative bacteria toward β-lactam antibiotics is caused by the interplay between four independent factors: i) the alteration of the sensitivity of the target enzymes, the penicillin-binding proteins, ii) the properties and concentration of the periplasmic β-lactamases, iii) the permeability of the outer membrane, iv) the efficiency of the active efflux system. On this basis, Zimmermann and Rosselet [1] proposed a model yelding a quantitative prediction of the MICs for gram-negative bacteria which was successfully applied to Escherichia coli and Enterobacter cloacae. This model seems to be less suitable in Pseudomonas aeruginosa due to its low outer membrane permeability which is mostly influenced by both a remarkable reduction of functional porins expression and an over-expression of efflux systems [2]. This decreased permeability causes difficulties in obtaining permeability coefficient direct measures. Moreover, the few published coefficients for P. aeruginosa are highly variable. For this purpose, BlaR-CTD, the C-terminal domain of a highly sensitive penicillin binding protein from Bacillus licheniformis, expressed in the periplasmic space, has been used in order to directly determinate of the concentrations of different β-lactams in this cell compartment and, consequently to obtain reliable measures of the permeability coefficient [3]. Methods P. aeruginosa PAO1 cells were incubated with different β-lactams, whose penetration into the periplasm is rapidly followed by the formation of a stable complex with BlaR-CTD. This latter was quantified in cells lysate by densitometric analysis, countermarking the free BlaR-CTD with a fluorescent β-lactam. The excess of the antibiotics will be hydrolysed by the addition of a class B β-lactamase. We used the same protocol for P. aeruginosa TNP004 [4], a PAO1 strain with a selective deletion of OprD porin, in order to study the influence of this single mutation for the antibiotic permeability. Results By the approach described above we determined the permeability coefficients of the external membrane of P. aeruginosa for different antibiotics belonging to the penicillin, cephalosporin and carbapenem sub-families. The comparison with the porin mutant strain showed similar coefficients for all the antibiotic tested except, as expected, for Imipenem Conclusion This work allowed a preliminary characterization of antibiotic permeability in P. aeruginosa which was poorly studied until now. Furthermore, we could apply this method to correlate the permeability with the role of porin deletions and/or efflux pumps overexpression in antibiotic resistant strains of clinical relevance. References 1 Zimmermann, W. and A. Rosselet. 1977. Function of the outer membrane of Escherichia coli as a permeability barrier to beta-lactam antibiotics. Antimicrob. Agents Chemother. 12:368–372. 2 Livermore D. M., and K. W. M. Davy. 1991. Invalidity for Pseudomonas aeruginosa of an accepted model of bacterial permeability to β-lactam antibiotics. Antimicrob. Agents Chemother. 35:916-921. 3 Lakaye B., Dubus A., Joris B., and J.M. Frère. 2002. Method for estimation of low outer membrane permeability to β-lactam antibiotics. Antimicrob. Agents Chemother. 46:2901-2907. 4 Yoneyama H., Yamano Y and T. Nakae. 1995 Role of porins in the antibiotic susceptibility of Pseudomonas aeruginosa: construction of mutants with deletions in the multiple porin genes. Biochem Biophys Res Commun. 213:88-95. [less ▲]

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See detail1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases
Sevaille, Laurent; Gavara, Laurent; Bebrone, Carine et al

in ChemMedChem (2017), 12

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL ... [more ▼]

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range. [less ▲]

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See detailInteraction of Avibactam with Class B Metallo-β-Lactamases.
Abboud, MI; Damblon, Christian ULiege; Brem, J et al

in Antimicrobial Agents and Chemotherapy (2016), 60

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See detailAnalysis of the Structure and Function of FOX-4 Cephamycinase
Lefurgy, S.T.; Malashkevich, V.N.; Aguilan, J.T. et al

in Antimicrobial Agents and Chemotherapy (2016), 60(2), 717-728

Class C β-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC β-lactamases conferring resistance to cefoxitin ... [more ▼]

Class C β-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC β-lactamases conferring resistance to cefoxitin, the FOX family, has grown to include nine unique members descended from the Aeromonas caviae chromosomal AmpC. To understand the basis for the unique cephamycinase activity in the FOX family, we determined the first X-ray crystal structures of FOX-4, apo enzyme and the acyl-enzyme with its namesake compound, cefoxitin, using the Y150F deacylation-deficient variant. Notably, recombinant expression of N-terminally tagged FOX-4 also yielded an inactive adenylylated enzyme form not previously observed in β-lactamases. The posttranslational modification (PTM), which occurs on the active site Ser64, would not seem to provide a selective advantage, yet might present an opportunity for the design of novel antibacterial drugs. Substantial ligand-induced changes in the enzyme are seen in the acyl-enzyme complex, particularly the R2 loop and helix H10 (P289 to N297), with movement of F293 by 10.3 Å. Taken together, this study provides the first picture of this highly proficient class C cephamycinase, uncovers a novel PTM, and suggests a possible cephamycin resistance mechanism involving repositioning of the substrate due to the presence of S153P, N289P, and N346I substitutions in the ligand binding pocket. [less ▲]

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See detailThe alarming increase in antibiotic-resistant bacteria
Frère, Jean-Marie ULiege; Rigali, Sébastien ULiege

in Drug Target Review (2016)

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See detailKinetics of the Interaction between BAL29880 and LK157 and the Class C β-Lactamase CHE-1
Fernea, Adriana; Galleni, Moreno ULiege; Frère, Jean-Marie ULiege

in Antimicrobial Agents and Chemotherapy (2016), 60

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See detailGram-Negative Bacteria: "Inner" vs. "Cytoplasmic" or "Plasma Membrane": A Question of Clarity rather than Vocabulary
Baurain, Denis ULiege; Wilmotte, Annick ULiege; Frère, Jean-Marie ULiege

in Journal of Microbial and Biochemical Technology (2016), 8(4), 325-326

In this short commentary, we show that the utilisation of the term “inner membrane” to characterize the cytoplasmic or plasma membrane of Gram-negative bacteria can be a source of confusion and we propose ... [more ▼]

In this short commentary, we show that the utilisation of the term “inner membrane” to characterize the cytoplasmic or plasma membrane of Gram-negative bacteria can be a source of confusion and we propose that it should be completely abandoned. [less ▲]

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See detailFrom "an enzyme able to destroy penicillin" to Carbapenemases: 70 Years of Beta-lactamase Misbehaviour
Frère, Jean-Marie ULiege; Sauvage, Eric ULiege; Kerff, Frederic ULiege

in Current Drug Targets (2016)

As early as 1940, Abraham and Chain described "an enzyme able to destroy penicillin". In the late 1940's, penicillin-resistant strains of Staphylococcus aureus were found to be a clinical problem. They ... [more ▼]

As early as 1940, Abraham and Chain described "an enzyme able to destroy penicillin". In the late 1940's, penicillin-resistant strains of Staphylococcus aureus were found to be a clinical problem. They produced a penicillinase that could hydrolyze the amide bond in the beta-lactam ring. Later, an enzyme mediated by an R-factor was isolated from Enterobacteriaceae. Methicillin and cephalosporins, both very poor substrates of the S. aureus enzyme, were found to be sensitive to this new enzyme. Third generation cephalosporins appeared to solve the problem, but further enzymes were selected that exhibited extended spectra and could for instance hydrolyze cefotaxime and/or ceftazidime. The discovery of carbapenems constituted a major advance for our antimicrobial arsenal: they inactivated most of the essential penicillin binding proteins effectively and escaped the activity of nearly all known beta-lactamases. However, the metallo-beta-lactamases, which had not been recognised as a major danger before 1990, were found to act as effective carbapenemases and started to spread in a worrying way. Moreover, carbapenem-hydrolyzing enzymes were found in each of the 3 classes of active-site serine beta-lactamases. [less ▲]

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See detailThe CebE/MsiK Transporter is a Doorway to the Cello-oligosaccharide-mediated Induction of Streptomyces scabies Pathogenicity
Jourdan, Samuel ULiege; Francis, Isolde; Kim, Min et al

in Scientific Reports (2016)

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See detailKinetics of the interaction between avibactam and the CHE-1 class C beta-lactamase
Fernea, Adriana; Galleni, Moreno ULiege; Frère, Jean-Marie ULiege

in Journal of Antimicrobial Chemotherapy (2015), 70(3), 951--953

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See detailPenicillin-binding proteins: evergreen drug targets.
Frère, Jean-Marie ULiege; Page, Malcolm G. P.

in Current Opinion in Pharmacology (2014), 18

The penicillin-binding proteins (PBPs) are well known targets for the beta-lactam antibiotics. They continue to be a focus of interest for pharmaceutical design, as exemplified by the number of new agents ... [more ▼]

The penicillin-binding proteins (PBPs) are well known targets for the beta-lactam antibiotics. They continue to be a focus of interest for pharmaceutical design, as exemplified by the number of new agents under clinical investigation as well as novel experimental molecules. Considerable advances have been made in understanding the structure and function of this family of enzymes, through high-resolution structural studies and mechanistic studies in solution. These studies have thrown light on role of the high molecular mass PBPs in mediating beta-lactam resistance, although much work remains to be done to enable a full description of the mechanisms by which these proteins modulate their sensitivity towards beta-lactams while retaining their essential activity in cell wall biosynthesis. [less ▲]

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See detailInhibition of Streptococcus pneumoniae pencillin-binding protein 2x and Actinomadura R39 DD-peptidase activities by ceftaroline.
Zervosen, Astrid ULiege; Zapun, Andre; Frère, Jean-Marie ULiege

in Antimicrobial Agents and Chemotherapy (2013), 57(1), 661-663

Although the rate of acylation of a penicillin-resistant form of Streptococcus pneumoniae PBP2x by ceftaroline is 80-fold lower than that of its penicillin-sensitive counterpart, it remains sufficiently ... [more ▼]

Although the rate of acylation of a penicillin-resistant form of Streptococcus pneumoniae PBP2x by ceftaroline is 80-fold lower than that of its penicillin-sensitive counterpart, it remains sufficiently high (k(2)/K = 12600 M(-1)s(-1)) to explain the sensitivity of the penicillin-resistant strain to this new cephalosporin. Surprisingly, the Actinomadura R39 DD-peptidase is not very sensitive to ceftaroline. [less ▲]

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