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  1. Article ; Online: The silver cation (Ag+): antistaphylococcal activity, mode of action and resistance studies.

    Randall, Christopher P / Oyama, Linda B / Bostock, Julieanne M / Chopra, Ian / O'Neill, Alex J

    The Journal of antimicrobial chemotherapy

    2013  Volume 68, Issue 1, Page(s) 131–138

    Abstract: Objectives: To examine several poorly understood or contentious aspects of the antibacterial activity of silver (Ag(+)), including its cidality, mode of action, the prevalence of resistance amongst clinical staphylococcal isolates and the propensity for ...

    Abstract Objectives: To examine several poorly understood or contentious aspects of the antibacterial activity of silver (Ag(+)), including its cidality, mode of action, the prevalence of resistance amongst clinical staphylococcal isolates and the propensity for Staphylococcus aureus to develop Ag(+) resistance.
    Methods: The effects of Ag(+) on the viability, macromolecular synthesis and membrane integrity of S. aureus SH1000 were assessed using established methodology. Silver nitrate MICs were determined for a collection of staphylococcal isolates (n = 1006) collected from hospitals across Europe and Canada between 1997 and 2010. S. aureus biofilms were grown using the Calgary Biofilm Device. To examine the in vitro development of staphylococcal resistance to Ag(+), bacteria were subjected to continuous subculture in the presence of sub-MIC concentrations of Ag(+).
    Results: Silver was bactericidal against S. aureus in buffered solution, but bacteriostatic in growth medium, and was unable to eradicate staphylococcal biofilms in vitro. Challenge of S. aureus with Ag(+) caused rapid loss of membrane integrity and inhibition of the major macromolecular synthetic pathways. All clinical staphylococcal isolates were susceptible to ≤ 16 mg/L silver nitrate and prolonged exposure (42 days) to Ag(+) in vitro failed to select resistant mutants.
    Conclusions: The rapid and extensive loss of membrane integrity observed upon challenge with Ag(+) suggests that the antibacterial activity results directly from damage to the bacterial membrane. The universal susceptibility of staphylococci to Ag(+), and failure to select for resistance to Ag(+), suggest that silver compounds remain a viable option for the prevention and treatment of topical staphylococcal infections.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Anti-Infective Agents, Local/pharmacology ; Biofilms/drug effects ; Biofilms/growth & development ; Culture Media ; Drug Resistance, Multiple, Bacterial/drug effects ; Drug Resistance, Multiple, Bacterial/physiology ; Humans ; Microbial Sensitivity Tests/methods ; Silver Nitrate/pharmacology ; Staphylococcus aureus/drug effects ; Staphylococcus aureus/growth & development
    Chemical Substances Anti-Bacterial Agents ; Anti-Infective Agents, Local ; Culture Media ; Silver Nitrate (95IT3W8JZE)
    Language English
    Publishing date 2013-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 191709-2
    ISSN 1460-2091 ; 0305-7453
    ISSN (online) 1460-2091
    ISSN 0305-7453
    DOI 10.1093/jac/dks372
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Mecillinam has potent in vitro activity against Chlamydophila pneumoniae ATCC VR1310.

    Bostock, Julieanne M / Geary, Ian / Eley, Adrian / Chopra, Ian

    The Journal of antimicrobial chemotherapy

    2004  Volume 53, Issue 6, Page(s) 1112

    MeSH term(s) Amdinocillin/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/metabolism ; Carrier Proteins/metabolism ; Cell Line ; Cephalosporins/pharmacology ; Chlamydophila pneumoniae/drug effects ; Hexosyltransferases/metabolism ; Microbial Sensitivity Tests ; Muramoylpentapeptide Carboxypeptidase/metabolism ; Penicillin-Binding Proteins ; Penicillins/pharmacology ; Peptidyl Transferases/metabolism
    Chemical Substances Anti-Bacterial Agents ; Bacterial Proteins ; Carrier Proteins ; Cephalosporins ; Penicillin-Binding Proteins ; Penicillins ; Peptidyl Transferases (EC 2.3.2.12) ; Hexosyltransferases (EC 2.4.1.-) ; Muramoylpentapeptide Carboxypeptidase (EC 3.4.17.8) ; Amdinocillin (V10579P3QZ)
    Language English
    Publishing date 2004-06
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 191709-2
    ISSN 1460-2091 ; 0305-7453
    ISSN (online) 1460-2091
    ISSN 0305-7453
    DOI 10.1093/jac/dkh233
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Zeocin resistance suppresses mutation in hypermutable Escherichia coli.

    Bostock, Julieanne M / Miller, Keith / O'Neill, Alexander J / Chopra, Ian

    Microbiology (Reading, England)

    2003  Volume 149, Issue Pt 4, Page(s) 815–816

    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Bleomycin/pharmacology ; Drug Resistance, Bacterial/genetics ; Escherichia coli/drug effects ; Escherichia coli/genetics ; Escherichia coli Proteins/genetics ; Microbial Sensitivity Tests ; Mutation ; Rifampin/pharmacology ; Suppression, Genetic
    Chemical Substances Anti-Bacterial Agents ; Escherichia coli Proteins ; Bleomycin (11056-06-7) ; Zeocin (181494-14-4) ; Rifampin (VJT6J7R4TR)
    Language English
    Publishing date 2003-02-14
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1180712-x
    ISSN 1465-2080 ; 1350-0872
    ISSN (online) 1465-2080
    ISSN 1350-0872
    DOI 10.1099/mic.0.C0111-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Assessment of a microplate method for determining the post-antibiotic effect in Staphylococcus aureus and Escherichia coli.

    Stubbings, William J / Bostock, Julieanne M / Ingham, Eileen / Chopra, Ian

    The Journal of antimicrobial chemotherapy

    2004  Volume 54, Issue 1, Page(s) 139–143

    Abstract: Objectives: The post-antibiotic effect (PAE) is an important parameter of antibiotic action that is widely used as a predictor of pharmacodynamic activity. Traditionally, PAE has been determined by a labour-intensive method involving determination of ... ...

    Abstract Objectives: The post-antibiotic effect (PAE) is an important parameter of antibiotic action that is widely used as a predictor of pharmacodynamic activity. Traditionally, PAE has been determined by a labour-intensive method involving determination of viable cell numbers. New methods using spectrophotometric procedures could offer significant advantages for PAE determinations, particularly in terms of speed. A number of such methods have been described in the literature, but extensive comparison with the classical procedure for determining PAEs has not been carried out. We have now compared PAE values obtained using a rapid microplate method with those achieved by the classical viable count procedure.
    Methods: We determined PAE values for a variety of antibiotics against Staphylococcus aureus and Escherichia coli following exposure to 5 x MIC drug concentrations for 60 min in Mueller-Hinton Broth (MHB). The duration of the PAE was obtained by following the recovery of bacterial growth in antibiotic-free MHB measured either as colony forming units on Mueller-Hinton agar, or as culture absorbance (600 nm) in a microplate reader.
    Results: For bacteriolytic agents there was poor correlation between the two methods for both S. aureus (R2=0.096) and E. coli (R2=0.5456). However, when PAEs for bacteriostatic agents and non-lytic bactericidal agents were compared, correlation between the two methods was high for both S. aureus (R2=0.7529) and E. coli (R2=0.7687).
    Conclusions: The spectrophotometric microplate method for determining PAEs may be a suitable alternative to the classical method for those antibiotics that do not induce bacterial cell lysis.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Colony Count, Microbial ; Culture Media ; Escherichia coli/drug effects ; Microbial Sensitivity Tests/methods ; Spectrophotometry, Infrared ; Staphylococcus aureus/drug effects
    Chemical Substances Anti-Bacterial Agents ; Culture Media
    Language English
    Publishing date 2004-07
    Publishing country England
    Document type Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 191709-2
    ISSN 1460-2091 ; 0305-7453
    ISSN (online) 1460-2091
    ISSN 0305-7453
    DOI 10.1093/jac/dkh275
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Discovery of new inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurF by structure-based virtual screening.

    Turk, Samo / Kovac, Andreja / Boniface, Audrey / Bostock, Julieanne M / Chopra, Ian / Blanot, Didier / Gobec, Stanislav

    Bioorganic & medicinal chemistry

    2009  Volume 17, Issue 5, Page(s) 1884–1889

    Abstract: The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys, and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the ...

    Abstract The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys, and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute 'Diversity Set' on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC(50)=10 microM) and one novel MurF inhibitor (IC(50)=63 microM).
    MeSH term(s) Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Computational Biology ; Computer Simulation ; Databases, Factual ; Drug Discovery ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Peptide Synthases/antagonists & inhibitors ; Peptide Synthases/chemistry ; Peptide Synthases/metabolism ; Peptidoglycan/biosynthesis
    Chemical Substances Anti-Bacterial Agents ; Enzyme Inhibitors ; Peptidoglycan ; Peptide Synthases (EC 6.3.2.-) ; UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase (EC 6.3.2.10)
    Language English
    Publishing date 2009-03-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2009.01.052
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Discovery of new inhibitors of D-alanine:D-alanine ligase by structure-based virtual screening.

    Kovac, Andreja / Konc, Janez / Vehar, Blaz / Bostock, Julieanne M / Chopra, Ian / Janezic, Dusanka / Gobec, Stanislav

    Journal of medicinal chemistry

    2008  Volume 51, Issue 23, Page(s) 7442–7448

    Abstract: The terminal dipeptide, D-Ala-D-Ala, of the peptidoglycan precursor UDPMurNAc-pentapetide is a crucial building block involved in peptidoglycan cross-linking. It is synthesized in the bacterial cytoplasm by the enzyme d-alanine:d-alanine ligase (Ddl). ... ...

    Abstract The terminal dipeptide, D-Ala-D-Ala, of the peptidoglycan precursor UDPMurNAc-pentapetide is a crucial building block involved in peptidoglycan cross-linking. It is synthesized in the bacterial cytoplasm by the enzyme d-alanine:d-alanine ligase (Ddl). Structure-based virtual screening of the NCI diversity set of almost 2000 compounds was performed with a DdlB isoform from Escherichia coli using the computational tool AutoDock 4.0. The 130 best-ranked compounds from this screen were tested in an in vitro assay for their inhibition of E. coli DdlB. Three compounds were identified that inhibit the enzyme with K(i) values in micromolar range. Two of these also have promising antibacterial activities against Gram-positive and Gram-negative bacteria.
    MeSH term(s) Catalytic Domain ; Computer Simulation ; Crystallography, X-Ray ; Drug Discovery ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Hydrogen Bonding ; Models, Chemical ; Models, Molecular ; Molecular Structure ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Peptide Synthases/antagonists & inhibitors ; Peptide Synthases/chemistry ; Structure-Activity Relationship
    Chemical Substances Enzyme Inhibitors ; Oligopeptides ; Peptide Synthases (EC 6.3.2.-) ; D-alanylalanine synthetase (EC 6.3.2.4)
    Language English
    Publishing date 2008-12-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm800726b
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Evolution of extended-spectrum beta-lactamases in a MutS-deficient Pseudomonas aeruginosa hypermutator.

    Driffield, Kiersten L / Bostock, Julieanne M / Miller, Keith / O'neill, Alexander J / Hobbs, Joanne K / Chopra, Ian

    The Journal of antimicrobial chemotherapy

    2006  Volume 58, Issue 4, Page(s) 905–907

    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Ceftazidime/pharmacology ; Cephalosporin Resistance ; Evolution, Molecular ; Humans ; Microbial Sensitivity Tests ; MutS DNA Mismatch-Binding Protein/genetics ; MutS DNA Mismatch-Binding Protein/metabolism ; Mutation ; Pseudomonas aeruginosa/enzymology ; Pseudomonas aeruginosa/genetics ; beta-Lactamases/genetics ; beta-Lactams/pharmacology
    Chemical Substances Anti-Bacterial Agents ; beta-Lactams ; Ceftazidime (9M416Z9QNR) ; beta-lactamase TEM-11 (EC 3.5.2.-) ; beta-lactamase TEM-61 (EC 3.5.2.-) ; beta-Lactamases (EC 3.5.2.6) ; MutS DNA Mismatch-Binding Protein (EC 3.6.1.3)
    Language English
    Publishing date 2006-10
    Publishing country England
    Document type Letter
    ZDB-ID 191709-2
    ISSN 1460-2091 ; 0305-7453
    ISSN (online) 1460-2091
    ISSN 0305-7453
    DOI 10.1093/jac/dkl324
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: A de novo designed inhibitor of D-Ala-D-Ala ligase from E. coli.

    Besong, Gilbert E / Bostock, Julieanne M / Stubbings, Will / Chopra, Ian / Roper, David I / Lloyd, Adrian J / Fishwick, Colin W G / Johnson, A Peter

    Angewandte Chemie (International ed. in English)

    2005  Volume 44, Issue 39, Page(s) 6403–6406

    MeSH term(s) Binding Sites ; Crystallography, X-Ray ; Cyclopropanes/chemical synthesis ; Cyclopropanes/chemistry ; Cyclopropanes/pharmacology ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Escherichia coli/enzymology ; Models, Molecular ; Molecular Conformation ; Peptide Synthases/antagonists & inhibitors ; Protein Conformation ; Software ; Structure-Activity Relationship
    Chemical Substances Cyclopropanes ; Enzyme Inhibitors ; cyclopropane (99TB643425) ; Peptide Synthases (EC 6.3.2.-) ; D-alanylalanine synthetase (EC 6.3.2.4)
    Language English
    Publishing date 2005-09-12
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.200501662
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  9. Article: Diazenedicarboxamides as inhibitors of D-alanine-D-alanine ligase (Ddl).

    Kovac, Andreja / Majce, Vita / Lenarsic, Roman / Bombek, Sergeja / Bostock, Julieanne M / Chopra, Ian / Polanc, Slovenko / Gobec, Stanislav

    Bioorganic & medicinal chemistry letters

    2007  Volume 17, Issue 7, Page(s) 2047–2054

    Abstract: D-Alanine-D-alanine ligase (Ddl) catalyzes the biosynthesis of an essential bacterial peptidoglycan precursor D-alanyl-D-alanine and it represents an important target for development of new antibacterial drugs. A series of semicarbazides, ... ...

    Abstract D-Alanine-D-alanine ligase (Ddl) catalyzes the biosynthesis of an essential bacterial peptidoglycan precursor D-alanyl-D-alanine and it represents an important target for development of new antibacterial drugs. A series of semicarbazides, aminocarbonyldiazenecarboxylates, diazenedicarboxamides, and hydrazinedicarboxamides was synthesized and screened for inhibition of DdlB from Escherichia coli. Compounds with good inhibitory activity were identified, enabling us to deduce initial structure-activity relationships. Thirteen diazenedicarboxamides were better inhibitors than D-cycloserine and some of them also possess antibacterial activity, which makes them a promising starting point for further development.
    MeSH term(s) Adenosine Diphosphate/chemistry ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Carboxylic Acids/chemistry ; Catalysis ; Chemistry, Pharmaceutical/methods ; Crystallography, X-Ray ; Cycloserine/chemistry ; Drug Design ; Escherichia coli/metabolism ; Imides/chemistry ; Imides/pharmacology ; Models, Chemical ; Molecular Conformation ; Peptide Synthases/antagonists & inhibitors ; Phosphorylation
    Chemical Substances Anti-Bacterial Agents ; Carboxylic Acids ; Imides ; Adenosine Diphosphate (61D2G4IYVH) ; Cycloserine (95IK5KI84Z) ; Peptide Synthases (EC 6.3.2.-) ; D-alanylalanine synthetase (EC 6.3.2.4) ; diazene (LM321PYV3Y)
    Language English
    Publishing date 2007-04-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2007.01.015
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  10. Article ; Online: The nature of Staphylococcus aureus MurA and MurZ and approaches for detection of peptidoglycan biosynthesis inhibitors.

    Blake, Katy L / O'Neill, Alex J / Mengin-Lecreulx, Dominique / Henderson, Peter J F / Bostock, Julieanne M / Dunsmore, Colin J / Simmons, Katie J / Fishwick, Colin W G / Leeds, Jennifer A / Chopra, Ian

    Molecular microbiology

    2009  Volume 72, Issue 2, Page(s) 335–343

    Abstract: Staphylococcus aureus and a number of other Gram-positive organisms harbour two genes (murA and murZ) encoding UDP-N-acetylglucosamine enolpyruvyl transferase activity for catalysing the first committed step of peptidoglycan biosynthesis. We ... ...

    Abstract Staphylococcus aureus and a number of other Gram-positive organisms harbour two genes (murA and murZ) encoding UDP-N-acetylglucosamine enolpyruvyl transferase activity for catalysing the first committed step of peptidoglycan biosynthesis. We independently inactivated murA and murZ in S. aureus and established that either can sustain viability. Purification and characterization of the MurA and MurZ enzymes indicated that they are biochemically similar in vitro, consistent with similar overall structures predicted for the isozymes by molecular modelling. Nevertheless, MurA appears to be the primary enzyme utilized in the staphylococcal cell. Accordingly, murA expression was approximately five times greater than murZ expression during exponential growth, and the peptidoglycan content of S. aureus was reduced by approximately 25% following inactivation of murA, but remained almost unchanged following inactivation of murZ. Despite low level expression during normal growth, murZ expression was strongly induced (up to sixfold) following exposure to inhibitors of peptidoglycan biosynthesis, which was not observed for murA. Strains generated in this study were validated as potential tools for identifying novel anti-staphylococcal agents targeting peptidoglycan biosynthesis using known inhibitors of the pathway.
    MeSH term(s) Alkyl and Aryl Transferases/genetics ; Alkyl and Aryl Transferases/metabolism ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Enzyme Inhibitors/pharmacology ; Fosfomycin/pharmacology ; Genes, Bacterial ; Models, Molecular ; Peptidoglycan/biosynthesis ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Sequence Deletion ; Staphylococcus aureus/drug effects ; Staphylococcus aureus/enzymology ; Staphylococcus aureus/genetics
    Chemical Substances Bacterial Proteins ; Enzyme Inhibitors ; Peptidoglycan ; Fosfomycin (2N81MY12TE) ; Alkyl and Aryl Transferases (EC 2.5.-) ; UDP-N-acetylglucosamine 1-carboxyvinyltransferase (EC 2.5.1.7)
    Language English
    Publishing date 2009-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 619315-8
    ISSN 1365-2958 ; 0950-382X
    ISSN (online) 1365-2958
    ISSN 0950-382X
    DOI 10.1111/j.1365-2958.2009.06648.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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