References of "Sauvage, Eric"
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See detailDynamic Distribution and Interaction of the Arabidopsis SRSF1 Subfamily Splicing Factors
Stankovic, Nancy ULg; Schloesser, Marie ULg; Joris, Marine ULg et al

in Plant Physiology (2016), 170

Serine/Arginine-rich (SR) proteins are essential nucleus-localized splicing factors. Our prior studies showed that Arabidopsis RSZ22, a homolog of the human SRSF7 SR factor, exits the nucleus through two ... [more ▼]

Serine/Arginine-rich (SR) proteins are essential nucleus-localized splicing factors. Our prior studies showed that Arabidopsis RSZ22, a homolog of the human SRSF7 SR factor, exits the nucleus through two pathways, either dependent or independent on the XPO1 receptor. Here, we examined the expression profiles and shuttling dynamics of the Arabidopsis SRSF1 subfamily (SR30, SR34, SR34a and SR34b) under control of their endogenous promoter in Arabidopsis and in transient expression assay. Due to its rapid nucleocytoplasmic shuttling and high expression level in transient assay, we analysed the multiple determinants that regulate the localisation and shuttling dynamics of SR34. By site-directed mutagenesis of SR34 RNA-binding sequences and RS domain, we further show that functional RRM1 or RRM2 are dispensable for the exclusive protein nuclear localization and speckle-like distribution. However, mutations of both RRMs induced aggregation of the protein whereas mutation in the RS domain decreased the stability of the protein and suppressed its nuclear accumulation. Furthermore, the RNA-binding motif mutants are defective for their export through the XPO1 (CRM1/Exportin-1) receptor pathway, but retain nucleocytoplasmic mobility. We performed a yeast two hybrid screen with SR34 as bait and discovered SR45 as a new interactor. SR45 is an unusual SR splicing factor bearing two RS domains. These interactions were confirmed in planta by FLIM-FRET and BiFC and the roles of SR34 domains in protein-protein interactions were further studied. Altogether, our report extends our understanding of shuttling dynamics of Arabidopsis SR splicing factors [less ▲]

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See detailOn the LZ distance for dereplicating redundant prokaryotic genomes
Léonard, Raphaël ULg; Baurain, Denis ULg; Kerff, Frédéric ULg et al

Poster (2015, December 07)

The fast-growing number of available prokaryotic genomes, along with their uneven taxonomic distribution, is a prob- lem when trying to assemble broadly sampled genome sets for phylogenomics and ... [more ▼]

The fast-growing number of available prokaryotic genomes, along with their uneven taxonomic distribution, is a prob- lem when trying to assemble broadly sampled genome sets for phylogenomics and comparative genomics. Indeed, most of the new genomes belong to the same subset of hyper-sampled phyla, such as Proteobacteria and Firmicutes, or even to single species, such as Escherichia coli (almost 2000 genomes as of Sept 2015), while the continuous flow of newly discovered phyla prompts for regular updates. This situation makes it difficult to maintain sets of representative genomes combining lesser known phyla, for which only few species are available, and sound subsets of highly abundant phyla. An automated straightforward method is required but none are publicly available. The LZ distance, in conjunction with the quality of the annotations, can be used to create an automated approach for selecting a subset of represen- tative genomes without redundancy. We are planning to release this tool on a website that will be made publicly available. [less ▲]

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See detailA lysine cluster in domain II of Bacillus subtilis PBP4a plays a role in the membrane attachment of this C1-PBP
Vanden Broeck, Arnaud; Van Der Heiden, Edwige ULg; Sauvage, Eric ULg et al

in PLoS ONE (2015)

In PBP4a, a Bacillus subtilis class-C1 penicillin-binding protein (PBP), four clustered lysine (K) residues, K86, K114, K119, and K265, protrude from domain II. Replacement of these amino acids with ... [more ▼]

In PBP4a, a Bacillus subtilis class-C1 penicillin-binding protein (PBP), four clustered lysine (K) residues, K86, K114, K119, and K265, protrude from domain II. Replacement of these amino acids with glutamine (Q) residues by site-directed mutagenesis yielded Mut4KQ PBP4a. When produced in Escherichia coli without its predicted Sec-signal peptide, wildtype (WT) PBP4a was found mainly associated with the host cytoplasmic membrane, whereas Mut4KQ PBP4a remained largely unbound. After purification, the capacities of the two proteins to bind to B. subtilis membranes were compared. The results were similar to those obtained in E. coli: in vitro, a much higher percentage of WT PBP4a than of Mut4KQ PBP4a was found to interact with B. subtilis membranes. Immunodetection of PBP4a in B. subtilis membrane extracts revealed that a processed form of this PBP (as indicated by its size) associates with the B. subtilis cytoplasmic membrane. In the absence of any amphiphilic peptide in PBP4a, the crown of positive charges on the surface of domain II is likely responsible for the cellular localization of this PBP and its attachment to the cytoplasmic membrane. [less ▲]

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See detailStructural and Kinetic Insights into the "Ceftazidimase" Behavior of the Extended-Spectrum beta-Lactamase CTX-M-96.
Ghiglione, Barbara; Rodriguez, Maria Margarita; Herman, Raphaël ULg et al

in Biochemistry (2015), 54(32), 5072-82

Diversification of the CTX-M beta-lactamases led to the emergence of variants responsible for decreased susceptibility to ceftazidime, like the Asp240Gly-harboring "ceftazidimases". We solved the ... [more ▼]

Diversification of the CTX-M beta-lactamases led to the emergence of variants responsible for decreased susceptibility to ceftazidime, like the Asp240Gly-harboring "ceftazidimases". We solved the crystallographic structure of the Asp240Gly variant CTX-M-96 at 1.2 A and evaluated the role of Asp240 in the activity toward oxyimino-cephalosporins through simulated models and kinetics. There seem to be subtle changes in the conformation of the active site cavity of CTX-M-96, compared to enzyme variants harboring the Asp240, and these small rearrangements could be due to localized shifts in the environment of the beta3 strand. According to the crystallographic evidence, CTX-M-96 presents a "compact" active site, which in spite of its reduced cavity seems to allow the proper interaction with oxyimino-cephalosporins, as suggested by simulated models. The term "ceftazidimases" that is currently applied for the Asp240Gly-harboring CTX-M variants should be used carefully. Structural differences between CTX-M harboring the Asp240Gly mutation (and also probably others like those at Pro167) do not seem to be conclusive to determine the "ceftazidimase" behavior observed in vivo, which is in turn partially supported by the mild improvement in the catalytic efficiency toward ceftazidime by CTX-M-96 and similar enzymes, compared to "parental" Asp240-harboring variants. In addition, it is observed that alterations in OmpF expression could act synergistically with CTX-M-96 for yielding clinical resistance toward ceftazidime. We therefore propose that the observed resistance in vivo is due to the sum of synergic mechanisms, and the term "cefotaximases associated with ceftazidime resistance" could be conveniently used to describe CTX-M harboring the Asp240Gly substitution. [less ▲]

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See detailFrom << An enzyme able to destroy penicillin >> to carbapenemases: 70 years of beta-lactamase misbehavior.
Frère, Jean-Marie ULg; Sauvage, Eric ULg; Kerff, Frederic ULg

in Current drug targets (2015)

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 detailStudies of the Domains II and III of Bacillus subtilis PBP4a in relation with the protein localization
Vanden Broeck, Arnaud ULg; Van Der Heiden, Edwige ULg; Sauvage, Eric ULg et al

Poster (2014, April 23)

Bacillus subtilis PBP4a belongs to the class-C1 PBPs characterized by two internal additional domains of unknown function. Seven lysine residues (K) are protruding from domain II. Four of them have been ... [more ▼]

Bacillus subtilis PBP4a belongs to the class-C1 PBPs characterized by two internal additional domains of unknown function. Seven lysine residues (K) are protruding from domain II. Four of them have been mutated in glutamine residues (Q). Both proteins (WT and Mut4KQ PBP4a) have been produced without signal peptide in E. coli and their sub-cellular localizations determined by measuring the DD-carboxypeptidase activities in the different compartments (cytoplasmic vs membrane attached proteins). In order to detect a possible influence of the PBP4a domain III in the localization of the protein, its encoding sequence has been cloned into pET-28b-BlaP, a vector allowing the production of WT BlaP β-lactamase or BlaP/DIII chimeric protein (with domain III inserted in a permissive loop of BlaP). The nitrocefin hydrolysis activities of BlaP or BlaP/DIII have been measured in the different cellular compartments. [less ▲]

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See detailCrystal structure of penicillin-binding protein 3 (PBP3) from Escherichia coli
Sauvage, Eric ULg; Derouaux, Adeline ULg; Fraipont, Claudine ULg et al

in PLoS ONE (2014)

In Escherichia coli, penicillin-binding protein 3 (PBP3), also known as FtsI, is a central component of the divisome, catalyzing cross-linking of the cell wall peptidoglycan during cell division. PBP3 is ... [more ▼]

In Escherichia coli, penicillin-binding protein 3 (PBP3), also known as FtsI, is a central component of the divisome, catalyzing cross-linking of the cell wall peptidoglycan during cell division. PBP3 is mainly periplasmic, with a 23 residues cytoplasmic tail and a single transmembrane helix. We have solved the crystal structure of a soluble form of PBP3 (PBP357-577) at 2.5 Å revealing the two modules of high molecular weight class B PBPs, a carboxy terminal module exhibiting transpeptidase activity and an amino terminal module with unknown function. To gain additional insight, the PBP3 Val88-Ser165 subdomain (PBP388-165), for which the electron density is poorly defined in the PBP3 crystal, was produced and its structure solved by SAD phasing at 2.1 Å. The structure shows a three dimensional domain swapping with a β-strand of one molecule inserted between two strands of the paired molecule, suggesting a possible role in PBP357-577 dimerization. [less ▲]

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See detailCrystal Structure of the Extended-Spectrum β -Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β -Lactams and β -Lactamase Inhibitors
Ruggiero, Melina; Kerff, Frédéric ULg; Herman, Raphaël ULg et al

in Antimicrobial Agents and Chemotherapy (2014), 58(10), 5994-6002

PER-2 belongs to a small (7 members to date) group of extended-spectrum beta-lactamases. It has 88% amino acid identity with PER-1 and both display high catalytic efficiencies toward most beta-lactams. In ... [more ▼]

PER-2 belongs to a small (7 members to date) group of extended-spectrum beta-lactamases. It has 88% amino acid identity with PER-1 and both display high catalytic efficiencies toward most beta-lactams. In this study, we determined the X-ray structure of PER-2 at 2.20 A and evaluated the possible role of several residues in the structure and activity toward beta-lactams and mechanism-based inhibitors. PER-2 is defined by the presence of a singular trans bond between residues 166 to 167, which generates an inverted Omega loop, an expanded fold of this domain that results in a wide active site cavity that allows for efficient hydrolysis of antibiotics like the oxyimino-cephalosporins, and a series of exclusive interactions between residues not frequently involved in the stabilization of the active site in other class A beta-lactamases. PER beta-lactamases might be included within a cluster of evolutionarily related enzymes harboring the conserved residues Asp136 and Asn179. Other signature residues that define these enzymes seem to be Gln69, Arg220, Thr237, and probably Arg/Lys240A ("A" indicates an insertion according to Ambler's scheme for residue numbering in PER beta-lactamases), with structurally important roles in the stabilization of the active site and proper orientation of catalytic water molecules, among others. We propose, supported by simulated models of PER-2 in combination with different beta-lactams, the presence of a hydrogen-bond network connecting Ser70-Gln69-water-Thr237-Arg220 that might be important for the proper activity and inhibition of the enzyme. Therefore, we expect that mutations occurring in these positions will have impacts on the overall hydrolytic behavior. [less ▲]

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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 ULg; Sauvage, Eric ULg 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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See detailInhibition of dd-Peptidases by a Specific Trifluoroketone: Crystal Structure of a Complex with the Actinomadura R39 dd-Peptidase.
Dzhekieva, Liudmila; Adediran, S. A.; Herman, Raphaël ULg et al

in Biochemistry (2013)

Inhibitors of bacterial dd-peptidases represent potential antibiotics. In the search for alternatives to beta-lactams, we have investigated a series of compounds designed to generate transition state ... [more ▼]

Inhibitors of bacterial dd-peptidases represent potential antibiotics. In the search for alternatives to beta-lactams, we have investigated a series of compounds designed to generate transition state analogue structures upon reaction with dd-peptidases. The compounds contain a combination of a peptidoglycan-mimetic specificity handle and a warhead capable of delivering a tetrahedral anion to the enzyme active site. The latter includes a boronic acid, two alcohols, an aldehyde, and a trifluoroketone. The compounds were tested against two low-molecular mass class C dd-peptidases. As expected from previous observations, the boronic acid was a potent inhibitor, but rather unexpectedly from precedent, the trifluoroketone [d-alpha-aminopimelyl(1,1,1-trifluoro-3-amino)butan-2-one] was also very effective. Taking into account competing hydration, we found the trifluoroketone was the strongest inhibitor of the Actinomadura R39 dd-peptidase, with a subnanomolar (free ketone) inhibition constant. A crystal structure of the complex between the trifluoroketone and the R39 enzyme showed that a tetrahedral adduct had indeed formed with the active site serine nucleophile. The trifluoroketone moiety, therefore, should be considered along with boronic acids and phosphonates as a warhead that can be incorporated into new and effective dd-peptidase inhibitors and therefore, perhaps, antibiotics. [less ▲]

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See detail2-nitrobenzyl esters of penam and cephem derivatives as inhibitors of penicillin-binding proteins
Brulé, Cédric; Grugier, Jérôme; Brans, Alain ULg et al

in Asian Journal of Organic Chemistry (2013), 2

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See detailMacrocyle-embedded b-lactams as novel inhibitors of the Penicillin Binding Protein PBP2a from MRSA
Dive, Georges ULg; Bouillon, Camille; Sliwa, Aline et al

in European Journal of Medicinal Chemistry (2013), 64

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See detailPeptidoglycan glycosyltransferase substrate mimics as templates for the design of new antibacterial drugs.
Derouaux, Adeline ULg; Sauvage, Eric ULg; Terrak, Mohammed ULg

in Frontiers in immunology (2013), 4

Peptidoglycan (PG) is an essential net-like macromolecule that surrounds bacteria, gives them their shape, and protects them against their own high osmotic pressure. PG synthesis inhibition leads to ... [more ▼]

Peptidoglycan (PG) is an essential net-like macromolecule that surrounds bacteria, gives them their shape, and protects them against their own high osmotic pressure. PG synthesis inhibition leads to bacterial cell lysis, making it an important target for many antibiotics. The final two reactions in PG synthesis are performed by penicillin-binding proteins (PBPs). Their glycosyltransferase (GT) activity uses the lipid II precursor to synthesize glycan chains and their transpeptidase (TP) activity catalyzes the cross-linking of two glycan chains via the peptide side chains. Inhibition of either of these two reactions leads to bacterial cell death. beta-lactam antibiotics target the transpeptidation reaction while antibiotic therapy based on inhibition of the GTs remains to be developed. Ongoing research is trying to fill this gap by studying the interactions of GTs with inhibitors and substrate mimics and utilizing the latter as templates for the design of new antibiotics. In this review we present an updated overview on the GTs and describe the structure-activity relationship of recently developed synthetic ligands. [less ▲]

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See detailSynthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C
Zervosen, Astrid ULg; Sauvage, Eric ULg; Bouillez, André ULg et al

Poster (2012, April 18)

The widespread use of beta-lactam antibiotics has lead to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to beta-lactams by three main mechanisms: the production of ... [more ▼]

The widespread use of beta-lactam antibiotics has lead to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to beta-lactams by three main mechanisms: the production of beta-lactamases that catalyze hydrolysis of beta-lactams, the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs) and the over expression of resistant PBPs. PBPs are interesting targets because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique in bacteria and has no mammalian analogs, outside the cytoplasmic membrane. Various non-ß-lactam inhibitors of PBPs have been developed with the objective of attempting to stall the development of ß-lactam resistance. Boronic acids are potent beta-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2, 6-dimethoxybenzamido)methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC50: 1.3 µM). Here, we will discuss the synthesis of a number of acylaminomethylboronic acids, analogs of (2, 6-dimethoxybenzamido)methylboronic acid, and their potential as inhibitors of PBPs. Several boronic acids of this library were able to inhibit PBPs of classes A, B and C from penicillin sensitive strains. Thus (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of class A PBP (PBP1b from S. pneumoniae, IC50 = 26 µM), class B PBP (PBP2xR6 from S. pneumoniae, IC50 = 138 µM) and class C PBP (R39 from Actinomadura sp., IC50 = 0.6 µM). Crystal structures of complexes of R39 and PBP1b with boronic acid analogs of our library have already been solved and allowed an interpretation of results. We believe that this work opens new avenues towards the development of molecules that will inhibit PBPs, and eventually display bactericidal effect, on distinct bacterial species. [less ▲]

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See detailNovel fragments of clavulanate observed in the structure of the class A b-lactamase from Bacillus licheniformis BS3
Power, Pablo; Mercuri, Paola ULg; Herman, Raphaël ULg et al

in Journal of Antimicrobial Chemotherapy (2012), 67(10), 2379-2387

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See detailDevelopment of new drugs for an old target — the penicillin binding proteins.
Zervosen, Astrid ULg; Sauvage, Eric ULg; Frère, Jean-Marie ULg et al

in Molecules (2012), 17(11), 12478-505

The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β ... [more ▼]

The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs). PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β-lactam resistance. These molecules are not susceptible to hydrolysis by β-lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and thus open avenues new for the discovery of novel antibiotics. [less ▲]

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See detailSynthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C.
Zervosen, Astrid ULg; Bouillez, André ULg; Herman, Alexandre et al

in Bioorganic & Medicinal Chemistry (2012), 20(12), 3915-24

In response to the widespread use of beta-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are ... [more ▼]

In response to the widespread use of beta-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are potent beta-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2,6-dimethoxybenzamido)methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC(50): 1.3muM). In this work, we synthesized and studied the potential of a number of acylaminomethylboronic acids as inhibitors of PBPs from different classes. Several derivatives inhibited PBPs of classes A, B and C from penicillin sensitive strains. The (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of a class A PBP (PBP1b from Streptococcus pneumoniae, IC(50)=26muM), a class B PBP (PBP2xR6 from Streptococcus pneumoniae, IC(50)=138muM) and a class C PBP (R39 from Actinomadura sp., IC(50)=0.6muM). This work opens new avenues towards the development of molecules that inhibit PBPs, and eventually display bactericidal effects, on distinct bacterial species. [less ▲]

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