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Sundin, Charlotta
Publications (10 of 21) Show all publications
Saleeb, M., Sundin, C., Aglar, Ö., Pinto, A. F., Ebrahimi, M., Forsberg, Å., . . . Elofsson, M. (2018). Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity. European Journal of Medicinal Chemistry, 143, 568-576
Open this publication in new window or tab >>Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 568-576Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
2-Aminobenzamide, ADP-Ribosyltransferase, Bacterial exotoxins, ExoS, Pseudomonas aeruginosa, Quinazolines, Type III secretion
National Category
Organic Chemistry Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-143429 (URN)10.1016/j.ejmech.2017.11.036 (DOI)000428216700046 ()29207339 (PubMedID)
Available from: 2017-12-23 Created: 2017-12-23 Last updated: 2018-08-24Bibliographically approved
Uusitalo, P., Hägglund, U., Rhöös, E., Norberg, H. S., Elofsson, M. & Sundin, C. (2017). The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo. Journal of antibiotics (Tokyo. 1968), 70(9), 937-943
Open this publication in new window or tab >>The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo
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2017 (English)In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 70, no 9, p. 937-943Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Japan Antibiotics Research Association, 2017
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-139127 (URN)10.1038/ja.2017.64 (DOI)000408401700003 ()28588224 (PubMedID)
Available from: 2017-10-06 Created: 2017-10-06 Last updated: 2018-06-09Bibliographically approved
Anantharajah, A., Faure, E., Buyck, J. M., Sundin, C., Lindmark, T., Mecsas, J., . . . Van Bambeke, F. (2016). Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation. Journal of Infectious Diseases, 214(7), 1105-1116
Open this publication in new window or tab >>Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation
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2016 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 7, p. 1105-1116Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2016
Keywords
Pseudomonas aeruginosa, type III secretion system, flagellum, pulmonary infection, cytotoxicity, flammasome activation, anti-virulence strategy
National Category
Immunology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-130110 (URN)10.1093/infdis/jiw295 (DOI)000386137800018 ()27412581 (PubMedID)
Available from: 2017-01-13 Created: 2017-01-11 Last updated: 2018-06-09Bibliographically approved
Davis, R. A., Beattie, K. D., Xu, M., Yang, X., Yin, S., Holla, H., . . . Quinn, R. J. (2014). Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type Ill secretion systems. Journal of natural products (Print), 77(12), 2633-2640
Open this publication in new window or tab >>Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type Ill secretion systems
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2014 (English)In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, no 12, p. 2633-2640Article in journal (Refereed) Published
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).

Place, publisher, year, edition, pages
Washington: American Chemical Society (ACS), 2014
Keywords
III secretion, pseudomonas aeruginosa, stem bark, chlamydia trachomatis, targeting virulence, stilbene oligomers, protein secretion, in vivo, yersinia, hopeaphenol
National Category
Chemical Sciences Biological Sciences
Identifiers
urn:nbn:se:umu:diva-104151 (URN)10.1021/np500433z (DOI)000347359900009 ()25405587 (PubMedID)
Available from: 2015-06-18 Created: 2015-06-08 Last updated: 2018-09-10Bibliographically approved
Enquist, P.-A., Gylfe, Å., Hägglund, U., Lindström, P., Norberg-Scherman, H., Sundin, C. & Elofsson, M. (2012). Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens. Bioorganic & Medicinal Chemistry Letters, 22(10), 3550-3553
Open this publication in new window or tab >>Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens
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2012 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 22, no 10, p. 3550-3553Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-54401 (URN)10.1016/j.bmcl.2012.03.096 (DOI)22525317 (PubMedID)
Note

Available online 6 April 2012

Available from: 2012-04-26 Created: 2012-04-25 Last updated: 2018-06-08Bibliographically approved
Yin, S., Davis, R. A., Shelper, T., Sykes, M. L., Avery, V. M., Elofsson, M., . . . Quinn, R. J. (2011). Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp. Organic and biomolecular chemistry, 9, 6755-6760
Open this publication in new window or tab >>Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp
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2011 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, p. 6755-6760Article in journal (Refereed) Published
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).

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-46062 (URN)10.1039/c1ob05581j (DOI)21850326 (PubMedID)
Available from: 2011-08-25 Created: 2011-08-25 Last updated: 2018-06-08Bibliographically approved
Veenendaal, A. K., Sundin, C. & Blocker, A. J. (2009). Small-molecule type III secretion system inhibitors block assembly of the Shigella type III secreton.. Journal of Bacteriology, 191(2), 563-70
Open this publication in new window or tab >>Small-molecule type III secretion system inhibitors block assembly of the Shigella type III secreton.
2009 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 191, no 2, p. 563-70Article in journal (Refereed) Published
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.

National Category
Natural Sciences
Identifiers
urn:nbn:se:umu:diva-135435 (URN)10.1128/JB.01004-08 (DOI)18996990 (PubMedID)
Available from: 2017-05-29 Created: 2017-05-29 Last updated: 2018-06-09
Sundin, C., Elofsson, M., Wolf-Watz, H. & Rosell, S. (2009). Virulensblockerande antibiotika: Antibakteriella medel med helt ny verkningsmekanism. Läkartidningen, 106(40), 2543-2545
Open this publication in new window or tab >>Virulensblockerande antibiotika: Antibakteriella medel med helt ny verkningsmekanism
2009 (English)In: Läkartidningen, Vol. 106, no 40, p. 2543-2545Article in journal (Other (popular science, discussion, etc.)) Published
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.

Identifiers
urn:nbn:se:umu:diva-26238 (URN)
Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2018-06-08Bibliographically approved
Kauppi, A. M., Andersson, D. C., Norberg, H. A., Sundin, C., Linusson Jonsson, A. & Elofsson, M. (2007). Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides. Bioorganic & Medicinal Chemistry, 15(22), 6994-7011
Open this publication in new window or tab >>Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 6994-7011Article in journal (Other academic) Published
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.

Place, publisher, year, edition, pages
Elsevier Ltd, 2007
Keywords
Type III secretion, Yersinia, Virulence, Inhibitors, Statistical molecular design: multivariate QSAR
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-5559 (URN)10.1016/j.bmc.2007.07.047 (DOI)
Note
Available online 22 August 2007 Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2018-06-09Bibliographically approved
Bailey, L., Gylfe, A., Sundin, C., Muschiol, S., Elofsson, M., Nordström, P., . . . Bergström, S. (2007). Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle. FEBS Lett, 581(4), 587-595
Open this publication in new window or tab >>Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle
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2007 (English)In: FEBS Lett, ISSN 0014-5793, Vol. 581, no 4, p. 587-595Article in journal (Refereed) Published
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.

Keywords
Animals, Anti-Bacterial Agents/chemistry/*pharmacology, Bacterial Proteins/*antagonists & inhibitors/genetics/*secretion, Cell Proliferation/drug effects, Chlamydia Infections/*microbiology, Chlamydia trachomatis/cytology/drug effects, Chlamydophila pneumoniae/cytology/*drug effects, Dose-Response Relationship; Drug, Down-Regulation/drug effects, Epithelial Cells/cytology/drug effects/microbiology, Gene Expression Regulation; Bacterial/drug effects, Genes; Bacterial, Hela Cells, Humans, Mice, Transcription; Genetic/drug effects, Yersinia Infections, Yersinia pseudotuberculosis/*drug effects
Identifiers
urn:nbn:se:umu:diva-12890 (URN)doi:10.1016/j.febslet.2007.01.013 (DOI)17257594 (PubMedID)
Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2018-06-09Bibliographically approved
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