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Caren Freel L Meyers - One of the best experts on this subject based on the ideXlab platform.

  • selective inhibition of e coli 1 deoxy d xylulose 5 phosphate synthase by acetylphosphonates
    MedChemComm, 2012
    Co-Authors: J M Smith, Ryan J Vierling, Caren Freel L Meyers
    Abstract:

    DXP synthase catalyzes the formation of 1-deoxy-D-xylulose 5-phosphate, an essential precursor in pathogen isoprenoid biosynthesis. The selective inhibition of this ThDP-dependent transformation is a challenging goal in the development of isoprenoid biosynthesis inhibitors. Potent, selective inhibitors could lead to new Anti-Infective Agents. Here, we demonstrate selective inhibition of E. coliDXP synthase by butylacetylphosphonate.

  • 1 deoxy d xylulose 5 phosphate synthase catalyzes a novel random sequential mechanism
    Journal of Biological Chemistry, 2011
    Co-Authors: Leighanne A Brammer, J M Smith, Herschel Wade, Caren Freel L Meyers
    Abstract:

    Emerging resistance of human pathogens to Anti-Infective Agents make it necessary to develop new Agents to treat infection. The methylerythritol phosphate pathway has been identified as an Anti-Infective target, as this essential isoprenoid biosynthetic pathway is widespread in human pathogens but absent in humans. The first enzyme of the pathway, 1-deoxy-d-xylulose 5-phosphate (DXP) synthase, catalyzes the formation of DXP via condensation of d-glyceraldehyde 3-phosphate (d-GAP) and pyruvate in a thiamine diphosphate-dependent manner. Structural analysis has revealed a unique domain arrangement suggesting opportunities for the selective targeting of DXP synthase; however, reports on the kinetic mechanism are conflicting. Here, we present the results of tryptophan fluorescence binding and kinetic analyses of DXP synthase and propose a new model for substrate binding and mechanism. Our results are consistent with a random sequential kinetic mechanism, which is unprecedented in this enzyme class.

Robert T. Clubb - One of the best experts on this subject based on the ideXlab platform.

  • discovery of staphylococcus aureus sortase a inhibitors using virtual screening and the relaxed complex scheme
    Chemical Biology & Drug Design, 2013
    Co-Authors: Albert H Chan, Michael E Jung, Brendan R Amer, Jeff Wereszczynski, Andrew J Mccammon, Robert T. Clubb
    Abstract:

    Staphylococcus aureus is the leading cause of hospital-acquired infections in the United States. The emergence of multidrug-resistant strains of S. aureus has created an urgent need for new antibiotics. Staphylococcus aureus uses the sortase A enzyme to display surface virulence factors suggesting that compounds that inhibit its activity will function as potent Anti-Infective Agents. Here, we report the identification of several inhibitors of sortase A using virtual screening methods that employ the relaxed complex scheme, an advanced computer-docking methodology that accounts for protein receptor flexibility. Experimental testing validates that several compounds identified in the screen inhibit the activity of sortase A. A lead compound based on the 2-phenyl-2,3-dihydro-1H-perimidine scaffold is particularly promising, and its binding mechanism was further investigated using molecular dynamics simulations and conducting preliminary structure-activity relationship studies.

  • discovery and structure activity relationship analysis of staphylococcus aureus sortase a inhibitors
    Bioorganic & Medicinal Chemistry, 2009
    Co-Authors: Nuttee Suree, William Thieu, Michael E Jung, Melanie Marohn, Robert Damoiseaux, Albert H Chan, Robert T. Clubb
    Abstract:

    Abstract Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent Anti-Infective Agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure–activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC 50 values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors.

  • the structure of the staphylococcus aureus sortase substrate complex reveals how the universally conserved lpxtg sorting signal is recognized
    Journal of Biological Chemistry, 2009
    Co-Authors: Nuttee Suree, Chu Kong Liew, Valerie A Villareal, William Thieu, Michael E Jung, Jeremy J. Clemens, E. A. Fadeev, Robert T. Clubb
    Abstract:

    In Gram-positive bacteria, sortase enzymes assemble surface proteins and pili in the cell wall envelope. Sortases catalyze a transpeptidation reaction that joins a highly conserved LPXTG sorting signal within their polypeptide substrate to the cell wall or to other pilin subunits. The molecular basis of transpeptidation and sorting signal recognition are not well understood, because the intermediates of catalysis are short lived. We have overcome this problem by synthesizing an analog of the LPXTG signal whose stable covalent complex with the enzyme mimics a key thioacyl catalytic intermediate. Here we report the solution structure and dynamics of its covalent complex with the Staphylococcus aureus SrtA sortase. In marked contrast to a previously reported crystal structure, we show that SrtA adaptively recognizes the LPXTG sorting signal by closing and immobilizing an active site loop. We have also used chemical shift mapping experiments to localize the binding site for the triglycine portion of lipid II, the second substrate to which surface proteins are attached. We propose a unified model of the transpeptidation reaction that explains the functions of key active site residues. Since the sortase-catalyzed anchoring reaction is required for the virulence of a number of bacterial pathogens, the results presented here may facilitate the development of new Anti-Infective Agents.

J M Smith - One of the best experts on this subject based on the ideXlab platform.

  • selective inhibition of e coli 1 deoxy d xylulose 5 phosphate synthase by acetylphosphonates
    MedChemComm, 2012
    Co-Authors: J M Smith, Ryan J Vierling, Caren Freel L Meyers
    Abstract:

    DXP synthase catalyzes the formation of 1-deoxy-D-xylulose 5-phosphate, an essential precursor in pathogen isoprenoid biosynthesis. The selective inhibition of this ThDP-dependent transformation is a challenging goal in the development of isoprenoid biosynthesis inhibitors. Potent, selective inhibitors could lead to new Anti-Infective Agents. Here, we demonstrate selective inhibition of E. coliDXP synthase by butylacetylphosphonate.

  • 1 deoxy d xylulose 5 phosphate synthase catalyzes a novel random sequential mechanism
    Journal of Biological Chemistry, 2011
    Co-Authors: Leighanne A Brammer, J M Smith, Herschel Wade, Caren Freel L Meyers
    Abstract:

    Emerging resistance of human pathogens to Anti-Infective Agents make it necessary to develop new Agents to treat infection. The methylerythritol phosphate pathway has been identified as an Anti-Infective target, as this essential isoprenoid biosynthetic pathway is widespread in human pathogens but absent in humans. The first enzyme of the pathway, 1-deoxy-d-xylulose 5-phosphate (DXP) synthase, catalyzes the formation of DXP via condensation of d-glyceraldehyde 3-phosphate (d-GAP) and pyruvate in a thiamine diphosphate-dependent manner. Structural analysis has revealed a unique domain arrangement suggesting opportunities for the selective targeting of DXP synthase; however, reports on the kinetic mechanism are conflicting. Here, we present the results of tryptophan fluorescence binding and kinetic analyses of DXP synthase and propose a new model for substrate binding and mechanism. Our results are consistent with a random sequential kinetic mechanism, which is unprecedented in this enzyme class.

Albert H Chan - One of the best experts on this subject based on the ideXlab platform.

  • nmr structure based optimization of staphylococcus aureus sortase a pyridazinone inhibitors
    Chemical Biology & Drug Design, 2017
    Co-Authors: Albert H Chan, Ethan M Weiner, Brendan R Amer, Christopher K Sue, Jeff Wereszczynski, Carly A Dillen, Silvia Senese, Jorge Z Torres, Andrew J Mccammon, Lloyd S Miller
    Abstract:

    Staphylococcus aureus is a leading cause of hospital-acquired infections in the USA and is a major health concern as methicillin-resistant S. aureus and other antibiotic-resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent Anti-Infective Agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches. Here we have used NMR spectroscopy to determine the molecular basis through which pyridazinone-based small molecules inhibit SrtA. These inhibitors covalently modify the active cysteine thiol and partially mimic the natural substrate of SrtA by inducing the closure of an active site loop. Computational and synthetic chemistry methods led to second-generation analogues that are ~70-fold more potent than the lead molecule. These optimized molecules exhibit broad-spectrum activity against other types of class A sortases, have reduced cytotoxicity, and impair SrtA-mediated protein display on S. aureus cell surface. Our work shows that pyridazinone analogues are attractive candidates for further development into Anti-Infective Agents, and highlights the utility of employing NMR spectroscopy and solubility-optimized small molecules in structure-based drug discovery.

  • discovery of staphylococcus aureus sortase a inhibitors using virtual screening and the relaxed complex scheme
    Chemical Biology & Drug Design, 2013
    Co-Authors: Albert H Chan, Michael E Jung, Brendan R Amer, Jeff Wereszczynski, Andrew J Mccammon, Robert T. Clubb
    Abstract:

    Staphylococcus aureus is the leading cause of hospital-acquired infections in the United States. The emergence of multidrug-resistant strains of S. aureus has created an urgent need for new antibiotics. Staphylococcus aureus uses the sortase A enzyme to display surface virulence factors suggesting that compounds that inhibit its activity will function as potent Anti-Infective Agents. Here, we report the identification of several inhibitors of sortase A using virtual screening methods that employ the relaxed complex scheme, an advanced computer-docking methodology that accounts for protein receptor flexibility. Experimental testing validates that several compounds identified in the screen inhibit the activity of sortase A. A lead compound based on the 2-phenyl-2,3-dihydro-1H-perimidine scaffold is particularly promising, and its binding mechanism was further investigated using molecular dynamics simulations and conducting preliminary structure-activity relationship studies.

  • discovery and structure activity relationship analysis of staphylococcus aureus sortase a inhibitors
    Bioorganic & Medicinal Chemistry, 2009
    Co-Authors: Nuttee Suree, William Thieu, Michael E Jung, Melanie Marohn, Robert Damoiseaux, Albert H Chan, Robert T. Clubb
    Abstract:

    Abstract Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent Anti-Infective Agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure–activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC 50 values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors.

Mark T. Hamann - One of the best experts on this subject based on the ideXlab platform.

  • role of marine natural products in the genesis of antiviral Agents
    Chemical Reviews, 2015
    Co-Authors: Vedanjali Gogineni, Raymond F Schinazi, Mark T. Hamann
    Abstract:

    Mammals have complex biological systems and are constantly prone to infections by a wide array of bacteria, fungi, viruses, and parasites, a significant challenge to the constant development of disease-strains resistance to current drugs.1 As a result, there is always a need to identify new Anti-Infective Agents against these organisms. An Anti-Infective agent is defined by Webster as “an agent capable of acting against an infection, by inhibiting the spread of an infectious agent or by killing the infectious agent outright”.2 Some of the emerging and drug-resistant infectious diseases having research priority are human immunodeficiency virus (HIV) or AIDS, hepatitis B and C viruses, respiratory infections such as influenza and respiratory syncytial virus (RSV), and dengue fever.1 Figures 1 and ​and22 provide us with the data in regards to the mortality and incidence rates, respectively, of people with viral diseases.3–5 Figure 1 Mortality versus viral diseases.3–5 Figure 2 Incidence rates versus viral diseases.3–5 Search engines utilized to identify the literature reviewed here include Google scholar, Scifinder, Pubmed, government documents from the CDC, NIH, and the World Health Organization (WHO), academic journals, and books.

  • Marine natural products and their potential applications as Anti-Infective Agents.
    The Lancet. Infectious diseases, 2003
    Co-Authors: Marwa S. Donia, Mark T. Hamann
    Abstract:

    The oceans are a unique resource that provide a diverse array of natural products, primarily from invertebrates such as sponges, tunicates, bryozoans, and molluscs, and from marine bacteria and cyanobacteria. As infectious diseases evolve and develop resistance to existing pharmaceuticals, the marine environment provides novel leads against fungal, parasitic, bacterial, and viral diseases. Many marine natural products have successfully advanced to the late stages of clinical trials, including dolastatin 10, ecteinascidin-743, kahalalide F, and aplidine, and a growing number of candidates have been selected as promising leads for extended preclinical assessment. Although many marine-product clinical trials are for cancer chemotherapy, drug resistance, emerging infectious diseases, and the threat of bioterrorism have all contributed to the interest in assessing natural ocean products in the treatment of infectious organisms. In this review, we focus on the pharmacologically tested marine leads that have shown in-vivo efficacy or potent in-vitro activity against infectious and parasitic diseases.