umu.sePublications
Change search
Refine search result
1 - 21 of 21
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Anantharajah, Ahalieyah
    et al.
    Faure, Emmanuel
    Buyck, Julien M.
    Sundin, Charlotta
    Creative Antibiotics, Umeå, Sweden .
    Lindmark, Tuulikki
    Mecsas, Joan
    Yahr, Timothy L.
    Tulkens, Paul M.
    Mingeot-Leclercq, Marie-Paule
    Guery, Benoît
    Van Bambeke, Françoise
    Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation2016In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 7, p. 1105-1116Article in journal (Refereed)
    Abstract [en]

    With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are 2 virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces interleukin 1 beta (IL-1 beta) release and reduces interleukin 17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis. Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination and IL-1 beta secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality, as evidenced by a reduction in secretory activity and flagellar motility and an increase in adenosine triphosphate levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising therapeutic approach.

  • 2.
    Bailey, Leslie
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gylfe, Asa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sundin, Charlotta
    Muschiol, Sandra
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Henriques-Normark, Birgitta
    Lugert, Raimond
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Molecular Biology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle2007In: FEBS Lett, ISSN 0014-5793, Vol. 581, no 4, p. 587-595Article in journal (Refereed)
    Abstract [en]

    Intracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs.

  • 3.
    Bröms, Jeanette
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Sundin, Charlotta
    Umeå University, Faculty of Medicine, Molecular Biology.
    Francis, Matthew
    Umeå University, Faculty of Medicine, Molecular Biology.
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Molecular Biology.
    Comparative analysis of type III effector translocation by Yersinia pseudotuberculosis expressing native LcrV or PcrV from Pseudomonas aeruginosa.2003In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 188, no 2, p. 239-249Article in journal (Refereed)
    Abstract [en]

    The homologues LcrV of Yersinia species and PcrV of Pseudomonas aeruginosa are pore-forming components. When expressed in a Yersinia lcrV background, PcrV formed smaller pores in infected erythrocyte membranes, correlating to a lowered translocation of Yersinia effectors. To understand this phenomenon, cytotoxins exoenzyme S of P. aeruginosa and YopE of Yersinia were introduced into a Yersinia background without Yop effectors but expressing LcrV or PcrV. Comparable translocation of each substrate indicated that substrate recognition by LcrV/PcrV is not a regulator of translocation. Yersinia harboring pcrV coexpressed with its native operon efficiently translocated effectors into HeLa cell monolayers and formed large LcrV-like pores in erythrocyte membranes. Thus, a PcrV complex with native P. aeruginosa translocon components is required to form fully functional pores for complete complementation of effector translocation in Yersinia.

  • 4. Davis, Rohan A.
    et al.
    Beattie, Karren D.
    Xu, Min
    Yang, Xinzhou
    Yin, Sheng
    Holla, Harish
    Healy, Peter C.
    Sykes, Melissa
    Shelper, Todd
    Avery, Vicky M.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Creative Antibiotics Sweden AB, Umeå, Sweden.
    Quinn, Ronald J.
    Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type Ill secretion systems2014In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, no 12, p. 2633-2640Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: The supply of (−)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screen- ing of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (−)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1−3 displayed IC50 values of 8.8, 12.5, and 9.9 μM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 μM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1−3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the β-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (−)-hopeaphenol (1).

  • 5.
    Enquist, Per-Anders
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Hägglund, Ulrik
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Lindström, Pia
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Norberg-Scherman, Henrik
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Sundin, Charlotta
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens2012In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 22, no 10, p. 3550-3553Article in journal (Refereed)
    Abstract [en]

    Small molecule screening identified 5-nitro-7-((4-phenylpiperazine-1-yl-)methyl)quinolin-8-ol INP1750 as a putative inhibitor of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. In this study we report structure-activity relationships for inhibition of T3S and show that the most potent compounds target both the extracellular bacterium Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis in cell-based infection models.

  • 6.
    Henriksson, Maria L.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Sundin, Charlotta
    Umeå University, Faculty of Medicine, Molecular Biology.
    Jansson, Anna L.
    Forsberg, Åke
    Palmer, Ruth H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hallberg, Bengt
    Exoenzyme S shows selective ADP-ribosylation and GTPase-activating protein (GAP) activities towards small GTPases in vivo2002In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 367, no 3, p. 617-28Article in journal (Refereed)
    Abstract [en]

    Intracellular targeting of the Pseudomonas aeruginosa toxins exoenzyme S (ExoS) and exoenzyme T (ExoT) initially results in disruption of the actin microfilament structure of eukaryotic cells. ExoS and ExoT are bifunctional cytotoxins, with N-terminal GTPase-activating protein (GAP) and C-terminal ADP-ribosyltransferase activities. We show that ExoS can modify multiple GTPases of the Ras superfamily in vivo. In contrast, ExoT shows no ADP-ribosylation activity towards any of the GTPases tested in vivo. We further examined ExoS targets in vivo and observed that ExoS modulates the activity of several of these small GTP-binding proteins, such as Ras, Rap1, Rap2, Ral, Rac1, RhoA and Cdc42. We suggest that ExoS is the major ADP-ribosyltransferase protein modulating small GTPase function encoded by P. aeruginosa. Furthermore, we show that the GAP activity of ExoS abrogates the activation of RhoA, Cdc42 and Rap1.

  • 7.
    Kauppi, Anna M.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Norberg, Henrik A.
    Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
    Sundin, Charlotta
    Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides2007In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 6994-7011Article in journal (Other academic)
    Abstract [en]

    Compound 1, 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-(3,4-dichloro-phenyl)-benzamide, was identified as a putative type III secretion inhibitor in Yersinia, and the compound thus has a potential to be used to prevent or treat bacterial infections. A set of seven analogues was synthesized and evaluated in a type III secretion dependent reporter-gene assay with viable bacterial to give basic SAR. A second set of 19 compounds was obtained by statistical molecular design in the building block and product space and subsequent synthesis. Evaluation in the reporter-gene assay showed that the compounds ranged from non-active to compounds more potent than 1. Based on the data multivariate QSAR models were established and the final Hi-PLS model showed good correlation between experimentally determined % inhibition and the calculated % inhibition of the reporter-gene signal.

  • 8. Muschiol, Sandra
    et al.
    Bailey, Leslie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gylfe, Asa
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hultenby, Kjell
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Normark, Staffan
    Henriques-Normark, Birgitta
    A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 39, p. 14566-14571Article in journal (Refereed)
    Abstract [en]

    The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3beta to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.

  • 9. Muschiol, Sandra
    et al.
    Bailey, Leslie
    Gylfe, Åsa
    Sundin, Charlotta
    Hultenby, Kjell
    Bergström, Sven
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Hans
    Normark, Staffan
    Henriques-Normark, Birgitta
    A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis2006In: National Academy of Sciences, USA: A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis, 2006, p. 14566-71Conference paper (Other academic)
    Abstract [en]

    The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3beta to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.

  • 10.
    Olsson, Ing-Marie
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Kauppi, Anna
    Norberg, Henrik
    Spjut, Sara
    Sundberg, Emma
    Gottfries, Johan
    Elofsson, Mikael
    Design, Synthesis and Biological Evaluation of a Set of Type III Secretion InhibitorsManuscript (Other academic)
    Abstract
  • 11.
    Saleeb, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Aglar, Öznur
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinto, Ana Filipa
    Ebrahimi, Mahsa
    Forsberg, Åke
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Schüler, Herwig
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity2018In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 568-576Article in journal (Refereed)
    Abstract [en]

    During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.

  • 12. Sundin, Charlotta
    et al.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rosell, Sune
    Virulensblockerande antibiotika: Antibakteriella medel med helt ny verkningsmekanism2009In: Läkartidningen, Vol. 106, no 40, p. 2543-2545Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Antibiotics are probably the most successful drugs ever. Despite this success bacterial diseases continue to plague mankind and an ever increasing number of bacteria become resistant to antibiotics in use today. There is an obvious need to turn the tide by development of novel antibacterial drugs. Such drugs should be based on new chemical scaffolds and target bacterial functions not yet explored in the clinic. Our knowledge on how bacteria cause disease has increased dramatically during the last decade. Highly sophisticated virulence systems enable the bacteria to evade host immune responses and establish infection. Virulence systems are pathogen specific and therefore constitute attractive targets for drug development. Small molecules that target virulence in several Gram-negative bacteria have been identified. These molecules, virulence blocking antibiotics, can be used against resistant bacteria and their specificity for the pathogen will spare the endogenous micro flora and thus reduce selection for resistance.

  • 13. Sundin, Charlotta
    et al.
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsberg, Ake
    ADP-ribosylation by exoenzyme T of Pseudomonas aeruginosa induces an irreversible effect on the host cell cytoskeleton in vivo.2004In: FEMS Microbiol Lett, ISSN 0378-1097, Vol. 234, no 1, p. 87-91Article in journal (Refereed)
    Abstract
  • 14.
    Sundin, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Hallberg, Bengt
    Forsberg, Åke
    ADP-ribosylation by Exoenzyme T of Pseudomonas aeruginosa induces an irreversible effect on the host cell cytoskeleton in vivoIn: Article in journal (Refereed)
    Abstract
  • 15.
    Sundin, Charlotta
    et al.
    Department of Microbiology, FOI NBC-Defence, Umeå.
    Henriksson, Maria L.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hallberg, Bengt
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Forsberg, Åke
    Department of Microbiology, FOI NBC-Defence, Umeå.
    Frithz-Lindsten, Elisabet
    Department of Microbiology, FOI NBC-Defence, Umeå.
    Exoenzyme T of Pseudomonas aeruginosa elicits cytotoxicity without interfering with Ras signal transduction2001In: Cellular Microbiology, Vol. 3, no 4, p. 237-46Article in journal (Refereed)
    Abstract [en]

    One virulence strategy used by the opportunistic pathogen Pseudomonas aeruginosa is to target toxic proteins into eukaryotic cells by a type III secretion mechanism. Two of these proteins, ExoS and ExoT, show 75% homology on amino acid level. However, compared with ExoS, ExoT exhibits highly reduced ADP-ribosylating activity and the role of ExoT in pathogenesis is poorly understood. To study the biological effect of ExoT, we used a strategy by which ExoT was delivered into host cells by the heterologous type III secretion system ofYersinia pseudotuberculosis. ExoT was found to induce a rounded cell morphology and to mediate disruption of actin microfilaments, similar to that induced by an ADP-ribosylation defective ExoS (E381A) and the related cytotoxin YopE of Y. pseudotuberculosis. In contrast to ExoS, ExoT had no major effect on cell viability and did not modify or inactivate Ras by ADP-ribosylation in vivo. However, similar to ExoS and YopE, ExoT exhibited GAP (GTPase activating protein) activity on RhoA GTPase in vitro. Interestingly, ExoT(R149K), deficient for GAP activity, still caused a morphological change of HeLa cells. Based on our findings, we suggest that the ADP-ribosylating activity of ExoT target another, as yet unidentified, host protein that is distinct from Ras.

  • 16.
    Sundin, Charlotta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Thelaus, Johanna
    Bröms, Jeanette E
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Polarisation of type III translocation by Pseudomonas aeruginosa requires PcrG, PcrV and PopN2004In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 37, no 6, p. 313-322Article in journal (Refereed)
    Abstract [en]

    Type III secretion (TTS) mediated translocation of exoenzymes is a key virulence strategy utilised by the opportunistic pathogen Pseudomonas aeruginosa to deliver exoenzyme effectors into the eukaryotic cell. We have previously shown that type III mediated translocation is a contact dependent process, which requires the secreted translocator proteins PerV, PopB and PopD. To further analyse this mechanism, HeLa cells were infected with the wild-type strain PAK as well as isogenic pcrV, popB, popD, pcrG and popN mutants. In the presence of eukaryotic cells, expression of exoenzyme S (ExoS) increased. When cells were infected with the wild-type strain PAK no ExoS was detected in the tissue culture medium. This confirms that ExoS translocation by P. aeruginosa occurs by a polarised mechanism. In contrast, high levels of ExoS were recovered in the tissue Culture medium when cells were infected with pcrG, pcrV and popN mutants. Additionally, ExoS expression levels were higher for these mutants regardless of inducing conditions. This suggests that PcrG, PcrV and PopN are involved in negative regulation of ExoS expression and secretion, and are required to ensure polarised delivery of effectors into target cells.

  • 17.
    Sundin, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Thelaus, Johanna
    Bröms, Jeanette E.
    Forsberg, Åke
    Polarised Type III Translocation of Effector Exoenzymes by Pseudomonas aeruginosaIn: Article in journal (Refereed)
    Abstract
  • 18.
    Sundin, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Wolfgang, Matthew C.
    Lory, Stephen
    Forsberg, Åke
    Frithz-Lindsten, Elisabet
    Type IV pili are not specifically required for contact dependent translocation of exoenzymes by Pseudomonas aeruginosa2002In: Microbial Pathogenesis, ISSN 0882-4010, Vol. 33, no 6, p. 265-77Article in journal (Refereed)
    Abstract
  • 19.
    Uusitalo, Pia
    et al.
    Creative Antibiotics AB, Umeå, Sweden.
    Hägglund, Ulrik
    Rhöös, Elin
    Norberg, Henrik Scherman
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Creative Antibiotics AB, Umeå, Sweden.
    The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo2017In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 70, no 9, p. 937-943Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa is an opportunistic pathogen that can be very hard to treat because of high resistance to different antibiotics and alternative treatment regimens are greatly needed. An alternative or a complement to traditional antibiotic is to inhibit virulence of the bacteria. The salicylidene acylhydrazide, INP0341, belongs to a class of compounds that has previously been shown to inhibit virulence in a number of Gram-negative bacteria. In this study, the virulence blocking effect of INP0341 on P. aeruginosa was studied in vitro and in vivo. Two important and closely related virulence system were examined, the type III secretion system (T3SS) that translocates virulence effectors into the cytosol of the host cell to evade immune defense and facilitate colonization and the flagella system, needed for motility and biofilm formation. INP0341 was shown to inhibit expression and secretion of the T3SS toxin exoenzyme S (ExoS) and to prevent bacterial motility on agar plates and biofilm formation. In addition, INP0341 showed an increased survival of P. aeruginosa-infected mice. In conclusion, INP0341 attenuates P. aeruginosa virulence.

  • 20. Veenendaal, Andreas K J
    et al.
    Sundin, Charlotta
    Blocker, Ariel J
    Small-molecule type III secretion system inhibitors block assembly of the Shigella type III secreton.2009In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 191, no 2, p. 563-70Article in journal (Refereed)
    Abstract [en]

    Type III secretion systems (T3SSs) are essential virulence devices for many gram-negative bacteria that are pathogenic for plants, animals, and humans. They serve to translocate virulence effector proteins directly into eukaryotic host cells. T3SSs are composed of a large cytoplasmic bulb and a transmembrane region into which a needle is embedded, protruding above the bacterial surface. The emerging antibiotic resistance of bacterial pathogens urges the development of novel strategies to fight bacterial infections. Therapeutics that rather than kill bacteria only attenuate their virulence may reduce the frequency or progress of resistance emergence. Recently, a group of salicylidene acylhydrazides were identified as inhibitors of T3SSs in Yersinia, Chlamydia, and Salmonella species. Here we show that these are also effective on the T3SS of Shigella flexneri, where they block all related forms of protein secretion so far known, as well as the epithelial cell invasion and induction of macrophage apoptosis usually demonstrated by this bacterium. Furthermore, we show the first evidence for the detrimental effect of these compounds on T3SS needle assembly, as demonstrated by increased numbers of T3S apparatuses without needles or with shorter needles. Therefore, the compounds generate a phenocopy of T3SS export apparatus mutants but with incomplete penetrance. We discuss why this would be sufficient to almost completely block the later secretion of effector proteins and how this begins to narrow the search for the molecular target of these compounds.

  • 21.
    Yin, Sheng
    et al.
    Eskitis Institute, Griffith University, Brisbane, Australia.
    Davis, Rohan A
    Eskitis Institute, Griffith University, Brisbane, Australia.
    Shelper, Todd
    Eskitis Institute, Griffith University, Brisbane, Australia.
    Sykes, Melissa L
    Eskitis Institute, Griffith University, Brisbane, Australia.
    Avery, Vicky M
    Eskitis Institute, Griffith University, Brisbane, Australia.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Creative Antibiotics Sweden AB, Umeå, Sweden.
    Quinn, Ronald J
    Eskitis Institute, Griffith University, Brisbane, Australia.
    Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp2011In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, p. 6755-6760Article in journal (Refereed)
    Abstract [en]

    Bioassay-guided fractionation of the CH(2)Cl(2)/MeOH extract of the Australian marine sponge Pseudoceratina sp. resulted in the purification of four new bromotyrosine alkaloids, pseudoceramines A-D (1-4), along with a known natural product, spermatinamine (5). The structures of 1-5 were determined by spectroscopic methods. Pseudoceramines A (1) and B (2) feature a rare bromotyrosyl-spermine-bromotyrosyl sequence, and pseudoceramine C (3) is the first example of bromotyrosine coupled with an N-methyl derivative of spermidine. Compounds 1-5 were screened for inhibition of toxin secretion by the type III secretion (T3S) pathway in Yersinia pseudotuberculosis. Compounds 2 and 5 inhibited secretion of the Yersinia outer protein YopE (IC(50) = 19 and 6 μM, respectively) and the enzyme activity of YopH (IC(50) = 33 and 6 μM, respectively).

1 - 21 of 21
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf