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Uvell, Hanna
Publications (10 of 13) Show all publications
Huerta-Uribe, A., Marjenberg, Z. R., Yamaguchi, N., Fitzgerald, S., Connolly, J. P. R., Carpena, N., . . . Roe, A. J. (2016). Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H7. Frontiers in Microbiology, 7, Article ID 1930.
Open this publication in new window or tab >>Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H7
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2016 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 7, article id 1930Article in journal (Refereed) Published
Abstract [en]

Infections caused by Shiga toxin-producing E. coli strains constitute a health problem, as they are problematic to treat. Shiga toxin (Stx) production is a key virulence factor associated with the pathogenicity of enterohaemorrhagic E. coli (EHEC) and can result in the development of haemolytic uremic syndrome in infected patients. The genes encoding Stx are located on temperate lysogenic phages integrated into the bacterial chromosome and expression of the toxin is generally coupled to phage induction through the SOS response. We aimed to find new compounds capable of blocking expression of Stx type 2 (Stx2) as this subtype of Stx is more strongly associated with human disease. High-throughput screening of a small-molecule library identified a lead compound that reduced Stx2 expression in a dose-dependent manner. We show that the optimised compound interferes with the SOS response by directly affecting the activity and oligomerisation of RecA, thus limiting phage activation and Stx2 expression. Our work suggests that RecA is highly susceptible to inhibition and that targeting this protein is a viable approach to limiting production of Stx2 by EHEC. This type of approach has the potential to limit production and transfer of other phage induced and transduced determinants.

Keywords
Shiga toxin, E. coli, RecA, phage, expression
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-128752 (URN)10.3389/fmicb.2016.01930 (DOI)000388897600001 ()
Available from: 2016-12-14 Created: 2016-12-14 Last updated: 2018-06-09Bibliographically approved
Hakala, E. F., Hanski, L., Uvell, H., Yrjonen, T., Vuorela, H., Elofsson, M. & Vuorela, P. M. (2015). Dibenzocyclooctadiene lignans from Schisandra spp. selectively inhibit the growth of the intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis. Journal of antibiotics (Tokyo. 1968), 68(10), 609-614
Open this publication in new window or tab >>Dibenzocyclooctadiene lignans from Schisandra spp. selectively inhibit the growth of the intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis
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2015 (English)In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 68, no 10, p. 609-614Article in journal (Refereed) Published
Abstract [en]

Lignans from Schisandra chinensis berries show various pharmacological activities, of which their antioxidative and cytoprotective properties are among the most studied ones. Here, the first report on antibacterial properties of six dibenzocyclooctadiene lignans found in Schisandra spp. is presented. The activity was shown on two related intracellular Gram-negative bacteria Chlamydia pneumoniae and Chlamydia trachomatis upon their infection in human epithelial cells. All six lignans inhibited C. pneumoniae inclusion formation and infectious progeny production. Schisandrin B inhibited C. pneumoniae inclusion formation even when administered 8 h post infection, indicating a target that occurs relatively late within the infection cycle. Upon infection, lignan-pretreated C. pneumoniae elementary bodies had impaired inclusion formation capacity. The presence and substitution pattern of methylenedioxy, methoxy and hydroxyl groups of the lignans had a profound impact on the antichlamydial activity. In addition our data suggest that the antichlamydial activity is not caused only by the antioxidative properties of the lignans. None of the compounds showed inhibition on seven other bacteria, suggesting a degree of selectivity of the antibacterial effect. Taken together, the data presented support a role of the studied lignans as interesting antichlamydial lead compounds.

National Category
Pharmaceutical Chemistry
Identifiers
urn:nbn:se:umu:diva-111766 (URN)10.1038/ja.2015.48 (DOI)000363879800003 ()25944533 (PubMedID)2-s2.0-84945309269 (Scopus ID)
Available from: 2015-11-24 Created: 2015-11-23 Last updated: 2018-06-07Bibliographically approved
Stylianou, M., Uvell, H., Lopes, J. P., Enquist, P.-A., Elofsson, M. & Urban, C. F. (2015). Novel High-Throughput Screening Method for Identification of Fungal Dimorphism Blockers. Journal of Biomolecular Screening, 20(2), 285-91
Open this publication in new window or tab >>Novel High-Throughput Screening Method for Identification of Fungal Dimorphism Blockers
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2015 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 20, no 2, p. 285-91Article in journal (Refereed) Published
Abstract [en]

Invasive mycoses have been increasing worldwide, with Candida spp. being the most prevalent fungal pathogen causing high morbidity and mortality in immunocompromised individuals. Only few antimycotics exist, often with severe side effects. Therefore, new antifungal drugs are urgently needed. Because the identification of antifungal compounds depends on fast and reliable assays, we present a new approach based on high-throughput image analysis to define cell morphology. Candida albicans and other fungi of the Candida clade switch between different growth morphologies, from budding yeast to filamentous hyphae. Yeasts are considered proliferative, whereas hyphae are required for invasion and dissemination. Thus, morphotype switching in many Candida spp. is connected to virulence and pathogenesis. It is, consequently, reasonable to presume that morphotype blockers interfere with the virulence, thereby preventing hazardous colonization. Our method efficiently differentiates yeast from hyphal cells using a combination of automated microscopy and image analysis. We selected the parameters length/width ratio and mean object shape to quantitatively discriminate yeasts and hyphae. Notably, Z' factor calculations for these parameters confirmed the suitability of our method for high-throughput screening. As a second stage, we determined cell viability to discriminate morphotype-switching inhibitors from those that are fungicidal. Thus, our method serves as a basis for the identification of candidates for next-generation antimycotics.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-101194 (URN)10.1177/1087057114552954 (DOI)000348642300012 ()25281739 (PubMedID)
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2018-08-01Bibliographically approved
Hanski, L., Genina, N., Uvell, H., Malinovskaja, K., Gylfe, A., Laaksonen, T., . . . Vuorela, P. M. (2014). Inhibitory Activity of the Isoflavone Biochanin A on Intracellular Bacteria of Genus Chlamydia and Initial Development of a Buccal Formulation. PLoS ONE, 9(12), Article ID e115115.
Open this publication in new window or tab >>Inhibitory Activity of the Isoflavone Biochanin A on Intracellular Bacteria of Genus Chlamydia and Initial Development of a Buccal Formulation
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, article id e115115Article in journal (Refereed) Published
Abstract [en]

Given the established role of Chlamydia spp. as causative agents of both acute and chronic diseases, search for new antimicrobial agents against these intracellular bacteria is required to promote human health. Isoflavones are naturally occurring phytoestrogens, antioxidants and efflux pump inhibitors, but their therapeutic use is limited by poor water-solubility and intense first-pass metabolism. Here, we report on effects of isoflavones against C. pneumoniae and C. trachomatis and describe buccal permeability and initial formulation development for biochanin A. Biochanin A was the most potent Chlamydia growth inhibitor among the studied isoflavones, ;with an IC50=12 mu M on C. pneumoniae inclusion counts and 6.5 mu M on infectious progeny production, both determined by immunofluorescent staining of infected epithelial cell cultures. Encouraged by the permeation of biochanin A across porcine buccal mucosa without detectable metabolism, oromucosal film formulations were designed and prepared by a solvent casting method. The film formulations showed improved dissolution rate of biochanin A compared to powder or a physical mixture, presumably due to the solubilizing effect of hydrophilic additives and presence of biochanin A in amorphous state. In summary, biochanin A is a potent inhibitor of Chlamydia spp., and the in vitro dissolution results support the use of a buccal formulation to potentially improve its bioavailability in antichlamydial or other pharmaceutical applications.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-100983 (URN)10.1371/journal.pone.0115115 (DOI)000349146300033 ()25514140 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-16 Last updated: 2018-06-07Bibliographically approved
Strand, M., Carlsson, M., Uvell, H., Islam, K., Edlund, K., Cullman, I., . . . Almqvist, F. (2014). Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria. Marine Drugs, 12(2), 799-821
Open this publication in new window or tab >>Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria
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2014 (English)In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 12, no 2, p. 799-821Article in journal (Refereed) Published
Abstract [en]

Adenovirus infections in immunocompromised patients are associated with high mortality rates. Currently, there are no effective anti-adenoviral therapies available. It is well known that actinobacteria can produce secondary metabolites that are attractive in drug discovery due to their structural diversity and their evolved interaction with biomolecules. Here, we have established an extract library derived from actinobacteria isolated from Vestfjorden, Norway, and performed a screening campaign to discover anti-adenoviral compounds. One extract with anti-adenoviral activity was found to contain a diastereomeric 1:1 mixture of the butenolide secondary alcohols 1a and 1b. By further cultivation and analysis, we could isolate 1a and 1b in different diastereomeric ratio. In addition, three more anti-adenoviral butenolides 2, 3 and 4 with differences in their side-chains were isolated. In this study, the anti-adenoviral activity of these compounds was characterized and substantial differences in the cytotoxic potential between the butenolide analogs were observed. The most potent butenolide analog 3 displayed an EC50 value of 91 μM and no prominent cytotoxicity at 2 mM. Furthermore, we propose a biosynthetic pathway for these compounds based on their relative time of appearance and structure.

Place, publisher, year, edition, pages
MDPI, 2014
Keywords
adenovirus; antiviral; natural products; secondary metabolites; marine actinobacteria; extract screening; butenolides
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-86525 (URN)10.3390/md12020799 (DOI)000335745100011 ()24477283 (PubMedID)
Available from: 2014-03-03 Created: 2014-02-28 Last updated: 2018-06-08Bibliographically approved
Marwaha, S., Uvell, H., Salin, O., Lindgren, A. E. G., Silver, J., Elofsson, M. & Gylfe, Å. (2014). N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis. Antimicrobial Agents and Chemotherapy, 58(5), 2968-2971
Open this publication in new window or tab >>N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis
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2014 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 5, p. 2968-2971Article in journal (Refereed) Published
Abstract [en]

Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

Place, publisher, year, edition, pages
American Society for Microbiology, 2014
National Category
Pharmaceutical Sciences Pharmacology and Toxicology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-89208 (URN)10.1128/AAC.02015-13 (DOI)000334364300064 ()
Available from: 2014-05-28 Created: 2014-05-26 Last updated: 2018-06-07Bibliographically approved
Dang, H. T., Chorell, E., Uvell, H., Pinkner, J. S., Hultgren, S. J. & Almqvist, F. (2014). Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives: antibacterial agents with antivirulence activity. Organic and biomolecular chemistry, 12(12), 1942-1956
Open this publication in new window or tab >>Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives: antibacterial agents with antivirulence activity
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2014 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, no 12, p. 1942-1956Article in journal (Refereed) Published
Abstract [en]

Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17 500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-87663 (URN)10.1039/c3ob42478b (DOI)000332225900014 ()
Available from: 2014-04-07 Created: 2014-04-07 Last updated: 2018-06-08Bibliographically approved
Larsson, M., Uvell, H., Sandström, J., Rydén, P., Selth, L. A. & Björklund, S. (2013). Functional Studies of the Yeast Med5, Med15 and Med16 Mediator Tail Subunits. PLoS ONE, 8(8), e73137
Open this publication in new window or tab >>Functional Studies of the Yeast Med5, Med15 and Med16 Mediator Tail Subunits
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e73137-Article in journal (Refereed) Published
Abstract [en]

The yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature-sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when Med5/15 or Med15/16 are inactivated together. We identify 25 genes in each double mutant that show a significant change in expression when compared to the corresponding single mutants and to the wild type strain. Importantly, 13 of the 25 identified genes are common for both double mutants. We also find that all strains in which MED15 is inactivated show down-regulation of genes that have been identified as targets for the Ace2 transcriptional activator protein, which is important for progression through the G1 phase of the cell cycle. Supporting this observation, we demonstrate that loss of Med15 leads to a G1 arrest phenotype. Collectively, these findings provide insight into the function of the Mediator Tail module.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-81837 (URN)10.1371/journal.pone.0073137 (DOI)000324470700057 ()
Available from: 2013-10-23 Created: 2013-10-22 Last updated: 2018-06-08Bibliographically approved
Bengtsson, C., Lindgren, A. E., Uvell, H. & Almqvist, F. (2012). Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents. European Journal of Medicinal Chemistry, 54, 637-646
Open this publication in new window or tab >>Design, synthesis and evaluation of triazole functionalized Ring-fused 2-pyridones as antibacterial agents
2012 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 54, p. 637-646Article in journal (Refereed) Published
Abstract [en]

Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities with EC50’s between 9-50 μM.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Pilicide, 2-Pyridone, Triazole, Huisgen 1, 3-dipolar cycloaddition, Antibacterial
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-56739 (URN)10.1016/j.ejmech.2012.06.018 (DOI)
Available from: 2012-06-26 Created: 2012-06-26 Last updated: 2018-06-08Bibliographically approved
Pohjala, L., Uvell, H., Hakala, E., Gylfe, Å., Elofsson, M. & Vuorela, P. (2012). The isoflavone biochanin a inhibits the growth of the intracellular bacteria Chiamydia trachomatis and Chlamydia pneumoniae. Paper presented at International Congress on Natural Products Research on Global Change, Natural Products and Human Health/8th Joint Meeting of AFERP, ASP, GA, PSE and SIF, JUL 28-AUG 01, 2012, New York, NY, USA. Planta Medica, 78(11), 1102-1102
Open this publication in new window or tab >>The isoflavone biochanin a inhibits the growth of the intracellular bacteria Chiamydia trachomatis and Chlamydia pneumoniae
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2012 (English)In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 78, no 11, p. 1102-1102Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Epidemiology and physiological consequences of chlamydial infections show these intracellular bacteria to have maintained their prevalence. Especially C. pneumoniae are able to confer to a treatment refractory chronic state of infection that cannot be eradicated with currently available therapeutic options. Here we report the effects of biochanin A on the growth of intracellular Chlamydia spp. It is the main flavonoid component of red clover (Trifolium pratense) extracts, which besides its estrogenic and antioxidative properties is known to potentiate the antibacterial effects of other chemical agents by inhibiting bacterial efflux pumps. We identified biochanin A as a hit compound in a high-content screen of purified natural products for C. trachomatis growth inhibitors. It was found to inhibit the replication of C. pneumoniae clinical strain K7 (IC =12μM) and to prevent 100% of infectious progeny production at 50μM. Thus, biochanin A is a more potent inhibitor of C. pneumoniae  than the related isoflavone genistein, which we have earlier shown to be only moderately active against this bacterium. Further, this data suggests that biochanin A acts as a direct growth inhibitor rather than an antibacterial potentiator against these pathogens.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2012
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-58911 (URN)10.1055/s-0032-1320490 (DOI)000307042800305 ()
Conference
International Congress on Natural Products Research on Global Change, Natural Products and Human Health/8th Joint Meeting of AFERP, ASP, GA, PSE and SIF, JUL 28-AUG 01, 2012, New York, NY, USA
Available from: 2012-09-07 Created: 2012-09-06 Last updated: 2018-06-08Bibliographically approved
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