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Albert J R Heck - One of the best experts on this subject based on the ideXlab platform.

  • Getting closer to the real Bacterial Cell Wall target: biomolecular interactions of water-soluble lipid II with glycopeptide antibiotics
    Chemistry: A European Journal, 2003
    Co-Authors: Pauline J Vollmerhaus, Eefjan Breukink, Albert J R Heck
    Abstract:

    : A novel synthesized water-soluble variant of lipid II (LII) was used to evaluate the noncovalent interactions between a number of glycopeptide antibiotics and their receptor by bioaffinity electrospray ionization mass spectrometry (ESI-MS). The water-soluble variant of lipid II is an improved design, compared to the traditionally used tripeptide N,N'-diacetyl-L-lysyl-D-alanyl-D-alanine (KAA), of the target molecule on the Bacterial Cell Wall. A representative group of glycopeptide antibiotics was selected for this study to evaluate the validity of the novel Cell-Wall-mimicking target LII. Structure-function relationships of various glycopeptide antibiotics were investigated by means of 1) bioaffinity mass spectrometry to evaluate solution-phase molecular interactions with both LII and KAA, 2) fluorescence leakage experiments to study the interactions with the membrane-embedded lipid II, and 3) minimum inhibitory concentrations against the indicator strain Micrococcus flavus. Our results with the novel LII molecule reveal that some antibiotics interact differently with KAA and LII. Additionally, our data cast doubt on the hypothesis that antibiotic selfdimerization assists in the in-vivo efficacy. Finally, the water-soluble lipid II proved to be a better model of the Bacterial Cell Wall.

  • interactions of α and β avoparcin with Bacterial Cell Wall receptor mimicking peptides studied by electrospray ionization mass spectrometry
    Journal of Antimicrobial Chemotherapy, 1999
    Co-Authors: Anca Van De Kerkvan Hoof, Albert J R Heck
    Abstract:

    Solution phase affinity constants of the glycopeptide antibiotic α- and β-avoparcin, with a range of Bacterial Cell-Wall receptor-mimicking model peptides, were determined by a relatively new method: affinity electrospray ionization mass spectrometry (ESI-MS). This method is relatively efficient and allows the parallel determination of several affinity constants in mixtures of antibiotics and receptors. The determined binding constants for α- and β-avoparcin were compared with those of the related glycopeptide antibiotic vancomycin. The solution phase binding affinities of α- and β-avoparcin on one hand, and vancomycin on the other, were found to be in the same order, at least for the range of receptor-mimicking peptides studied. However, β-avoparcin displayed slightly higher binding affinities than α-avoparcin, particularly for strong binding receptor-mimicking peptides. The evidence that α- and β-avoparcin and vancomycin are structurally similar, combined with the present data revealing their similar affinity for Bacterial Cell-Wall receptor-mimicking peptides, supports the hypothesis that the appearance of vancomycin-resistant enterococci (VRE) might be linked to the widespread use of avoparcin.

  • original articles interactions of and avoparcin with Bacterial Cell Wall receptor mimicking peptides studied by electrospray ionization mass spectrometry
    1999
    Co-Authors: Kerkvan Hoof, Albert J R Heck, Spectrometry Bijvoet
    Abstract:

    Solution phase affinity constants of the glycopeptide antibiotic - and -avoparcin, with a range of Bacterial Cell-Wall receptor-mimicking model peptides, were determined by a relatively new method: affinity electrospray ionization mass spectrometry (ESI-MS). This method is relatively efficient and allows the parallel determination of several affinity constants in mixtures of antibiotics and receptors. The determined binding constants for - and -avoparcin were compared with those of the related glycopeptide antibiotic vancomycin. The solution phase binding affinities of - and -avoparcin on one hand, and vancomycin on the other, were found to be in the same order, at least for the range of receptor-mimi cking peptides studied. However, -avoparcin displayed slightly higher binding affinities than -avoparcin, particularly for strong binding receptor-mimicking peptides. The evidence that - and -avoparcin and vancomycin are structurally similar, combined with the present data revealing their similar affinity for Bacterial Cell-Wall receptor-mimicking peptides, supports the hypothesis that the appearance of vancomycin-resistant enterococci (VRE) might be linked to the widespread use of avoparcin.

Andrea Dessen - One of the best experts on this subject based on the ideXlab platform.

  • penicillin binding proteins pbps and Bacterial Cell Wall elongation complexes
    Sub-cellular biochemistry, 2019
    Co-Authors: Mayara Mayele Miyachiro, Carlos Contrerasmartel, Andrea Dessen
    Abstract:

    The Bacterial Cell Wall is the validated target of mainstream antimicrobials such as penicillin and vancomycin. Penicillin and other β-lactams act by targeting Penicillin-Binding Proteins (PBPs), enzymes that play key roles in the biosynthesis of the main component of the Cell Wall, the peptidoglycan. Despite the spread of resistance towards these drugs, the Bacterial Cell Wall continues to be a major Achilles’ heel for microbial survival, and the exploration of the Cell Wall formation machinery is a vast field of work that can lead to the development of novel exciting therapies. The sheer complexity of the Cell Wall formation process, however, has created a significant challenge for the study of the macromolecular interactions that regulate peptidoglycan biosynthesis. New developments in genetic and biochemical screens, as well as different aspects of structural biology, have shed new light on the importance of complexes formed by PBPs, notably within the Cell Wall elongation machinery. This chapter summarizes structural and functional details of PBP complexes involved in the periplasmic and membrane steps of peptidoglycan biosynthesis with a focus on Cell Wall elongation. These assemblies could represent interesting new targets for the eventual development of original antiBacterials.

  • Molecular architecture of the PBP2–MreC core Bacterial Cell Wall synthesis complex
    Nature Communications, 2017
    Co-Authors: Carlos Contreras-martel, Alexandre Martins, Chantal Ecobichon, Daniel Maragno Trindade, Pierre-jean Matteï, Samia Hicham, Pierre Hardouin, Meriem El Ghachi, Ivo G. Boneca, Andrea Dessen
    Abstract:

    Bacterial Cell Wall biosynthesis is an essential process that requires the coordinated activity of peptidoglycan biosynthesis enzymes within multi-protein complexes involved in Cell division (the “divisome”) and lateral Wall growth (the “elongasome”). MreC is a structural protein that serves as a platform during Wall elongation, scaffolding other essential peptidoglycan biosynthesis macromolecules, such as penicillin-binding proteins. Despite the importance of these multi-partite complexes, details of their architecture have remained elusive due to the transitory nature of their interactions. Here, we present the crystal structures of the soluble PBP2:MreC core elongasome complex from Helicobacter pylori, and of uncomplexed PBP2. PBP2 recognizes the two-winged MreC molecule upon opening of its N-terminal region, revealing a hydrophobic zipper that serves as binding platform. The PBP2:MreC interface is essential both for protein recognition in vitro and maintenance of Bacterial shape and growth. This work allows visualization as to how peptidoglycan machinery proteins are scaffolded, revealing interaction regions that could be targeted by tailored inhibitors.

  • Structural Insights into Protein-Protein Interactions Involved in Bacterial Cell Wall Biogenesis.
    Antibiotics (Basel Switzerland), 2016
    Co-Authors: Federica Laddomada, Mayara Mayele Miyachiro, Andrea Dessen
    Abstract:

    The Bacterial Cell Wall is essential for survival, and proteins that participate in its biosynthesis have been the targets of antibiotic development efforts for decades. The biosynthesis of its main component, the peptidoglycan, involves the coordinated action of proteins that are involved in multi-member complexes which are essential for Cell division (the "divisome") and/or Cell Wall elongation (the "elongasome"), in the case of rod-shaped Cells. Our knowledge regarding these interactions has greatly benefitted from the visualization of different aspects of the Bacterial Cell Wall and its cytoskeleton by cryoelectron microscopy and tomography, as well as genetic and biochemical screens that have complemented information from high resolution crystal structures of protein complexes involved in divisome or elongasome formation. This review summarizes structural and functional aspects of protein complexes involved in the cytoplasmic and membrane-related steps of peptidoglycan biosynthesis, with a particular focus on protein-protein interactions whereby disruption could lead to the development of novel antiBacterial strategies.

  • Resistance to antibiotics targeted to the Bacterial Cell Wall
    Protein Science, 2014
    Co-Authors: Ioanis Nikolaidis, S. Favini-stabile, Andrea Dessen
    Abstract:

    Peptidoglycan is the main component of the Bacterial Cell Wall. It is a complex, three-dimensional mesh that surrounds the entire Cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antiBacterials. Synthesis of the peptidoglycan occurs sequentially within three Cellular compartments (cytoplasm, membrane, and periplasm), and inhibi-tors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the under-standing of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target Bacterial Cell Wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed.

Shahriar Mobashery - One of the best experts on this subject based on the ideXlab platform.

  • Constructing and deconstructing the Bacterial Cell Wall
    Protein science : a publication of the Protein Society, 2019
    Co-Authors: J. F. Fisher, Shahriar Mobashery
    Abstract:

    The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antiBacterial antibiotics disproportionately target Bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for Bacterial Cell-Wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre-eminent class of antibiotics-the β-lactams, exemplified by the penicillins and cephalosporins-from the perspective of the evolving mechanisms for Bacterial resistance. The mechanism of action of the β-lactams is Bacterial Cell-Wall destruction. In the monoderm (single membrane, Gram-positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β-lactam-unreactive transpeptidase enzyme that functions in Cell-Wall construction. In the diderm (dual membrane, Gram-negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β-lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between Cell-Wall construction and Cell-Wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β-lactams. This review summarizes how the β-lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.

  • Lytic transglycosylases: concinnity in concision of the Bacterial Cell Wall.
    Critical reviews in biochemistry and molecular biology, 2017
    Co-Authors: David A. Dik, J. F. Fisher, Daniel R. Marous, Shahriar Mobashery
    Abstract:

    The lytic transglycosylases (LTs) are Bacterial enzymes that catalyze the non-hydrolytic cleavage of the peptidoglycan structures of the Bacterial Cell Wall. They are not catalysts of glycan synthesis as might be surmised from their name. Notwithstanding the seemingly mundane reaction catalyzed by the LTs, their lytic reactions serve bacteria for a series of astonishingly diverse purposes. These purposes include Cell-Wall synthesis, remodeling, and degradation; for the detection of Cell-Wall-acting antibiotics; for the expression of the mechanism of Cell-Wall-acting antibiotics; for the insertion of secretion systems and flagellar assemblies into the Cell Wall; as a virulence mechanism during infection by certain Gram-negative bacteria; and in the sporulation and germination of Gram-positive spores. Significant advances in the mechanistic understanding of each of these processes have coincided with the successive discovery of new LTs structures. In this review, we provide a systematic perspective on what is known on the structure-function correlations for the LTs, while simultaneously identifying numerous opportunities for the future study of these enigmatic enzymes.

  • Reactions of all Escherichia coli lytic transglycosylases with Bacterial Cell Wall.
    Journal of the American Chemical Society, 2013
    Co-Authors: Mijoon Lee, Dusan Hesek, Leticia I. Llarrull, Elena Lastochkin, Bill Boggess, Shahriar Mobashery
    Abstract:

    The reactions of all seven Escherichia coli lytic transglycosylases with purified Bacterial sacculus are characterized in a quantitative manner. These reactions, which initiate recycling of the Bacterial Cell Wall, exhibit significant redundancy in the activities of these enzymes along with some complementarity. These discoveries underscore the importance of the functions of these enzymes for recycling of the Cell Wall.

  • Messenger Functions of the Bacterial Cell Wall-derived Muropeptides
    Biochemistry, 2012
    Co-Authors: Marc A. Boudreau, J. F. Fisher, Shahriar Mobashery
    Abstract:

    Bacterial muropeptides are soluble peptidoglycan structures central to recycling of the Bacterial Cell Wall and messengers in diverse Cell signaling events. Bacteria sense muropeptides as signals that antibiotics targeting Cell-Wall biosynthesis are present, and eukaryotes detect muropeptides during the innate immune response to Bacterial infection. This review summarizes the roles of Bacterial muropeptides as messengers, with a special emphasis on Bacterial muropeptide structures and the relationship of structure to the biochemical events that the muropeptides elicit. Muropeptide sensing and recycling in both Gram-positive and Gram-negative bacteria are discussed, followed by muropeptide sensing by eukaryotes as a crucial event in the innate immune response of insects (via peptidoglycan-recognition proteins) and mammals (through Nod-like receptors) to Bacterial invasion.

  • Thermodynamics of interactions of vancomycin and synthetic surrogates of Bacterial Cell Wall.
    Journal of the American Chemical Society, 2006
    Co-Authors: Mikhail V. Rekharsky, Dusan Hesek, Samy O Meroueh, Mijoon Lee, Yoshihisa Inoue, Shahriar Mobashery
    Abstract:

    Glycopeptide antibiotics, including vancomycin, form complexes via a set of five hydrogen bonds with the acyl-l-Lys-d-Ala-d-Ala portion of the peptidyl stems of the Bacterial Cell Wall peptidoglycan. This complexation deprives the organism from the ability to cross-link peptidyl stems of the peptidoglycan, leading to Bacterial Cell death. Four synthetic fragments as surrogates of the components of the Bacterial Cell Wall have been prepared in our lab in multistep syntheses. These synthetic samples were used in investigations of the thermodynamics properties (ΔG°, ΔH°, and TΔS°) for the complexation with vancomycin by isothermal titration calorimetry (ITC). Complexation with the glycopeptide analogues is largely enthalpy-driven (formation of five hydrogen bonds), and in the analogues with a single peptidyl stem, the complexation is 1:1. The complexation is more complicated with an approximately 2 kDa Cell Wall surrogate (compound 4), which possesses two peptidyl stems. The data were suggestive of interacti...

Stanislav Gobec - One of the best experts on this subject based on the ideXlab platform.

  • Table_1_Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis.pdf
    2019
    Co-Authors: Marko Jukič, Kaja Rožman, Matej Sova, Hélène Barreteau, Stanislav Gobec
    Abstract:

    We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of Bacterial Cell Wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antiBacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antiBacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μg/mL).

  • Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis
    Frontiers in Microbiology, 2018
    Co-Authors: Marko Jukič, Kaja Rožman, Matej Sova, Hélène Barreteau, Stanislav Gobec
    Abstract:

    We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of Bacterial Cell Wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antiBacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antiBacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μg/mL).

Hélène Barreteau - One of the best experts on this subject based on the ideXlab platform.

  • Table_1_Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis.pdf
    2019
    Co-Authors: Marko Jukič, Kaja Rožman, Matej Sova, Hélène Barreteau, Stanislav Gobec
    Abstract:

    We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of Bacterial Cell Wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antiBacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antiBacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μg/mL).

  • Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis
    Frontiers in Microbiology, 2018
    Co-Authors: Marko Jukič, Kaja Rožman, Matej Sova, Hélène Barreteau, Stanislav Gobec
    Abstract:

    We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of Bacterial Cell Wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antiBacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antiBacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μg/mL).

  • deciphering the metabolism of undecaprenyl phosphate the Bacterial Cell Wall unit carrier at the membrane frontier
    Microbial Drug Resistance, 2014
    Co-Authors: Guillaume Manat, Hélène Barreteau, Sophie Roure, Rodolphe Auger, Ahmed Bouhss, Dominique Menginlecreulx, Thierry Touze
    Abstract:

    During the biogenesis of Bacterial Cell-Wall polysaccharides, such as peptidoglycan, cytoplasmic synthesized precursors should be trafficked across the plasma membrane. This essential process requires a dedicated lipid, undecaprenyl-phosphate that is used as a glycan lipid carrier. The sugar is linked to the lipid carrier at the inner face of the membrane and is translocated toward the periplasm, where the glycan moiety is transferred to the growing polymer. Undecaprenyl-phosphate originates from the dephosphorylation of its precursor undecaprenyl-diphosphate, with itself generated by de novo synthesis or by recycling after the final glycan transfer. Undecaprenyl-diphosphate is de novo synthesized by the cytosolic cis-prenyltransferase undecaprenyl-diphosphate synthase, which has been structurally and mechanistically characterized in great detail highlighting the condensation process. In contrast, the next step toward the formation of the lipid carrier, the dephosphorylation step, which has been overlooke...