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Publications (10 of 116) Show all publications
Zambelloni, R., Beckham, K. S., Wu, H.-J., Elofsson, M., Marquez, R., Gabrielsen, M. & Roe, A. J. (2022). Crystal structures of WrbA, a spurious target of the salicylidene acylhydrazide inhibitors of type III secretion in Gram-negative pathogens, and verification of improved specificity of next-generation compounds. Microbiology, 168(7), Article ID 001211.
Open this publication in new window or tab >>Crystal structures of WrbA, a spurious target of the salicylidene acylhydrazide inhibitors of type III secretion in Gram-negative pathogens, and verification of improved specificity of next-generation compounds
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2022 (English)In: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 168, no 7, article id 001211Article in journal (Refereed) Published
Abstract [en]

The enterohemorrhagic Escherichia coli pathotype is responsible for severe and dangerous infections in humans. Establishment of the infection requires colonization of the gastro-intestinal tract, which is dependent on the Type III Secretion System. The Type III Secretion System (T3SS) allows attachment of the pathogen to the mammalian host cell and cytoskeletal rearrangements within the host cell. Blocking the functionality of the T3SS is likely to reduce colonization and therefore limit the disease. This route offers an alternative to antibiotics, and problems with the development of antibiotics resistance. Salicylidene acylhydrazides have been shown to have an inhibitory effect on the T3SS in several pathogens. However, the main target of these compounds is still unclear. Past work has identified a number of putative protein targets of these compounds, one of which being WrbA. Whilst WrbA is considered an off-target interaction, this study presents the effect of the salicylidne acylhydrazide compounds on the activity of WrbA, along with crystal structures of WrbA from Yersinia pseudotuberculosis and Salmonella serovar Typhimurium; the latter also containing parts of the compound in the structure. We also present data showing that the original compounds were unstable in acidic conditions, and that later compounds showed improved stability.

Place, publisher, year, edition, pages
Microbiology Society, 2022
Keywords
flavin mononucleotide, inhibition, protein structure, type III secretion
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-198298 (URN)10.1099/mic.0.001211 (DOI)2-s2.0-85134435193 (Scopus ID)
Available from: 2022-07-29 Created: 2022-07-29 Last updated: 2022-07-29Bibliographically approved
Johansson, E., Caraballo, R., Zocher, G., Mistry, N., Arnberg, N., Stehle, T. & Elofsson, M. (2022). Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction. RSC Advances, 12(4), 2319-2331
Open this publication in new window or tab >>Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction
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2022 (English)In: RSC Advances, E-ISSN 2046-2069, Vol. 12, no 4, p. 2319-2331Article in journal (Refereed) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) is responsible for several outbreaks and two pandemics of the highly contagious eye infection acute hemorrhagic conjunctivitis (AHC). Currently, neither prevention (vaccines) nor treatments (antivirals) are available for combating this disease. CVA24v attaches to cells by binding Neu5Ac-containing glycans on the surface of cells which facilitates entry. Previously, we have demonstrated that pentavalent Neu5Ac conjugates attenuate CVA24v infection of human corneal epithelial (HCE) cells. In this study, we report on the structure-based design of three classes of divalent Neu5Ac conjugates, with varying spacer lengths, and their effect on CVA24v transduction in HCE cells. In relative terms, the most efficient class of divalent Neu5Ac conjugates are more efficient than the pentavalent Neu5Ac conjugates previously reported.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2022
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-192370 (URN)10.1039/d1ra08968d (DOI)000742407000001 ()2-s2.0-85123934421 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2022-02-11 Created: 2022-02-11 Last updated: 2022-09-15Bibliographically approved
Beyer, S., Kimani, M., Zhang, Y., Verhassel, A., Sternbæk, L., Wang, T., . . . Stollenwerk, M. M. (2022). Fluorescent Molecularly Imprinted Polymer Layers against Sialic Acid on Silica-Coated Polystyrene Cores — Assessment of the Binding Behavior to Cancer Cells. Cancers, 14(8), Article ID 1875.
Open this publication in new window or tab >>Fluorescent Molecularly Imprinted Polymer Layers against Sialic Acid on Silica-Coated Polystyrene Cores — Assessment of the Binding Behavior to Cancer Cells
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2022 (English)In: Cancers, ISSN 2072-6694, Vol. 14, no 8, article id 1875Article in journal (Refereed) Published
Abstract [en]

Sialic acid (SA) is a monosaccharide usually linked to the terminus of glycan chains on the cell surface. It plays a crucial role in many biological processes, and hypersialylation is a common feature in cancer. Lectins are widely used to analyze the cell surface expression of SA. However, these protein molecules are usually expensive and easily denatured, which calls for the development of alternative glycan-specific receptors and cell imaging technologies. In this study, SA-imprinted fluorescent core-shell molecularly imprinted polymer particles (SA-MIPs) were employed to recognize SA on the cell surface of cancer cell lines. The SA-MIPs improved suspensibility and scattering properties compared with previously used core-shell SA-MIPs. Although SA-imprinting was performed using SA without preference for the α2,3-and α2,6-SA forms, we screened the cancer cell lines analyzed using the lectins Maackia Amurensis Lectin I (MAL I, α2,3-SA) and Sambucus Nigra Lectin (SNA, α2,6-SA). Our results show that the selected cancer cell lines in this study presented a varied binding behavior with the SA-MIPs. The binding pattern of the lectins was also demonstrated. Moreover, two different pentavalent SA conjugates were used to inhibit the binding of the SA-MIPs to breast, skin, and lung cancer cell lines, demonstrating the specificity of the SA-MIPs in both flow cytometry and confocal fluorescence microscopy. We concluded that the synthesized SA-MIPs might be a powerful future tool in the diagnostic analysis of various cancer cells.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
cancer, imprinting, molecularly imprinted polymers, SA conjugates, sialic acid
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-194273 (URN)10.3390/cancers14081875 (DOI)000786858400001 ()2-s2.0-85127781436 (Scopus ID)
Available from: 2022-04-29 Created: 2022-04-29 Last updated: 2023-09-05Bibliographically approved
Johansson, E., Caraballo, R., Hurdiss, D. L., Mistry, N., Andersson, C. D., Thompson, R. F., . . . Elofsson, M. (2021). Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates. International Journal of Molecular Sciences, 22(16), Article ID 8418.
Open this publication in new window or tab >>Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates
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2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 16, article id 8418Article in journal (Refereed) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
5-N-acetylneuraminic acid, Antivirals, Conjunctivitis, Coxsackievirus A24v, Cryo-EM, Multivalency, Sialic acid conjugates
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-186555 (URN)10.3390/ijms22168418 (DOI)000689130700001 ()2-s2.0-85111762142 (Scopus ID)
Available from: 2021-08-11 Created: 2021-08-11 Last updated: 2023-09-05Bibliographically approved
Sundin, C., Saleeb, M., Spjut, S., Qin, L. & Elofsson, M. (2021). Identification of small molecules blocking the Pseudomonas aeruginosa type III secretion system protein PcrV. Biomolecules, 11(1), Article ID 55.
Open this publication in new window or tab >>Identification of small molecules blocking the Pseudomonas aeruginosa type III secretion system protein PcrV
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2021 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 1, article id 55Article in journal (Refereed) Published
Abstract [en]

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that employs its type III secretion system (T3SS) during the acute phase of infection to translocate cytotoxins into the host cell cytoplasm to evade the immune system. The PcrV protein is located at the tip of the T3SS, facilitates the integration of pore-forming proteins into the eukaryotic cell membrane, and is required for translocation of cytotoxins into the host cell. In this study, we used surface plasmon resonance screening to identify small molecule binders of PcrV. A follow-up structure-activity relationship analysis resulted in PcrV binders that protect macrophages in a P. aeruginosa cell-based infection assay. Treatment of P. aeruginosa infections is challenging due to acquired, intrinsic, and adaptive resistance in addition to a broad arsenal of virulence systems such as the T3SS. Virulence blocking molecules targeting PcrV constitute valuable starting points for development of next generation antibacterials to treat infections caused by P. aeruginosa. 

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Pseudomonas aeruginosa, type III secretion, PcrV, surface plasmon resonance, screening, small molecules, macrophages, virulence inhibitors, infection
National Category
Organic Chemistry Microbiology in the medical area
Research subject
Organic Chemistry; biology
Identifiers
urn:nbn:se:umu:diva-150969 (URN)10.3390/biom11010055 (DOI)000609855400001 ()33406810 (PubMedID)2-s2.0-85099098899 (Scopus ID)
Funder
Swedish Foundation for Strategic Research , SB12-0022
Note

Originally included in thesis in manuscript form.

Available from: 2018-08-21 Created: 2018-08-21 Last updated: 2023-03-24Bibliographically approved
El-Schich, Z., Zhang, Y., Göransson, T., Dizeyi, N., Persson, J. L., Johansson, E., . . . Wingren, A. G. (2021). Sialic acid as a biomarker studied in breast cancer cell lines in vitro using fluorescent molecularly imprinted polymers. Applied Sciences, 11(7), Article ID 3256.
Open this publication in new window or tab >>Sialic acid as a biomarker studied in breast cancer cell lines in vitro using fluorescent molecularly imprinted polymers
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2021 (English)In: Applied Sciences, E-ISSN 2076-3417, Vol. 11, no 7, article id 3256Article in journal (Refereed) Published
Abstract [en]

Sialylations are post-translational modifications of proteins and lipids that play important roles in many cellular events, including cell-cell interactions, proliferation, and migration. Tumor cells express high levels of sialic acid (SA), which are often associated with the increased invasive potential in clinical tumors, correlating with poor prognosis. To overcome the lack of natural SA-receptors, such as antibodies and lectins with high enough specificity and sensitivity, we have used molecularly imprinted polymers (MIPs), or “plastic antibodies”, as nanoprobes. Because high expression of epithelial cell adhesion molecule (EpCAM) in primary tumors is often associated with proliferation and a more aggressive phenotype, the expression of EpCAM and CD44 was initially analyzed. The SA-MIPs were used for the detection of SA on the cell surface of breast cancer cells. Lectins that specifically bind to the a-2,3 SA and a-2,6 SA variants were used for analysis of SA expression, with both flow cytometry and confocal microscopy. Here we show a correlation of EpCAM and SA expression when using the SA-MIPs for detection of SA. We also demonstrate the binding pattern of the SA-MIPs on the breast cancer cell lines using confocal microscopy. Pre-incubation of the SA-MIPs with SA-derivatives as inhibitors could reduce the binding of the SA-MIPs to the tumor cells, indicating the specificity of the SA-MIPs. In conclusion, the SA-MIPs may be a new powerful tool in the diagnostic analysis of breast cancer cells.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Breast cancer, Epithelial cell adhesion molecule, Molecularly imprinted polymers, Nanoparticles, Sialic acid
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-182753 (URN)10.3390/app11073256 (DOI)000638354600001 ()2-s2.0-85104259855 (Scopus ID)
Available from: 2021-05-24 Created: 2021-05-24 Last updated: 2023-09-05Bibliographically approved
Johansson, E., Caraballo, R. & Elofsson, M. (2021). Synthesis of 4-O-alkylated N-acetylneuraminic acid derivatives. Journal of Organic Chemistry, 86(13), 9145-9154
Open this publication in new window or tab >>Synthesis of 4-O-alkylated N-acetylneuraminic acid derivatives
2021 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 13, p. 9145-9154Article in journal (Refereed) Published
Abstract [en]

The synthesis of 4-O-alkyl analogs of N-acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described. Activated alkyl halides and sulfonates and primary alkyl iodides give products in useful yields. The utility of the methodology is exemplified using a thiophenyl Neu5Ac building block to synthesize a 4-O-alkyl DANA analog. These results expand the toolbox of Neu5Ac chemistry with value in drug discovery and for the design of novel tools to study the biology of Neu5Ac lectins. 

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-182319 (URN)10.1021/acs.joc.1c00235 (DOI)000670661000052 ()34138565 (PubMedID)2-s2.0-85110169034 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2021-04-19 Created: 2021-04-19 Last updated: 2024-01-03Bibliographically approved
Gwon, Y.-D., Strand, M., Lindquist, R., Nilsson, E., Saleeb, M., Elofsson, M., . . . Evander, M. (2020). Antiviral Activity of Benzavir-2 against Emerging Flaviviruses. Viruses, 12(3), Article ID 351.
Open this publication in new window or tab >>Antiviral Activity of Benzavir-2 against Emerging Flaviviruses
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2020 (English)In: Viruses, E-ISSN 1999-4915, Vol. 12, no 3, article id 351Article in journal (Refereed) Published
Abstract [en]

Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA- and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC50 value of 0.8 +/- 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
benzavir-2, flavivirus, Zika virus, antiviral drugs
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-174282 (URN)10.3390/v12030351 (DOI)000525486800013 ()32235763 (PubMedID)2-s2.0-85082528703 (Scopus ID)
Funder
Swedish Research Council, 2016–06251
Available from: 2020-08-20 Created: 2020-08-20 Last updated: 2024-01-17Bibliographically approved
Sharma, P., Elofsson, M. & Roy, S. (2020). Attenuation of Pseudomonas aeruginosa infection by INP0341, a salicylidene acylhydrazide, in a murine model of keratitis. Virulence, 11(1), 795-804
Open this publication in new window or tab >>Attenuation of Pseudomonas aeruginosa infection by INP0341, a salicylidene acylhydrazide, in a murine model of keratitis
2020 (English)In: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 11, no 1, p. 795-804Article in journal (Refereed) Published
Abstract [en]

Pseudomonas aeruginosa: is an opportunistic pathogen and a major cause of corneal infections worldwide. The bacterium secretes several toxins through its type III secretion system (T3SS) to subvert host immune responses. In addition, it is armed with intrinsic as well as acquired antibiotic resistance mechanisms that make treatment a significant challenge and new therapeutic interventions are needed. Type III secretion inhibitors have been studied as an alternative or in accompaniment to traditional antibiotics to inhibit virulence of bacteria. In this study, INP0341, a T3SS inhibitor, inhibited cytotoxicity by P. aeruginosa toward human corneal epithelial cells (HCEC) at 100 μM without affecting bacterial growth in the liquid media. An increased expression of antimicrobial peptides and reactive oxygen species generation was also observed in cells exposed to P. aeruginosa in the presence of INP0341. Furthermore, INP0341 efficiently attenuated corneal infection by P. aeruginosa in an experimental model of murine keratitis as evident from corneal opacity, clinical score and bacterial load. Thus, INP0341 appears to be a promising candidate to treat corneal infection caused by P. aeruginosa and can be further considered as an alternative therapeutic intervention.

Place, publisher, year, edition, pages
Taylor & Francis, 2020
Keywords
Antimicrobial peptides, corneal epithelial cells, INP0341, Pseudomonas aeruginosa, reactive oxygen species, type III secretion system
National Category
Immunology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-197896 (URN)10.1080/21505594.2020.1776979 (DOI)2-s2.0-85086296629 (Scopus ID)
Available from: 2022-07-08 Created: 2022-07-08 Last updated: 2023-03-24Bibliographically approved
Sundin, C., Zetterström, C. E., Vo, D. D., Brkljača, R., Urban, S. & Elofsson, M. (2020). Exploring resveratrol dimers as virulence blocking agent: Attenuation of type III secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa. Scientific Reports, 10(1), Article ID 2103.
Open this publication in new window or tab >>Exploring resveratrol dimers as virulence blocking agent: Attenuation of type III secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 2103Article in journal (Refereed) Published
Abstract [en]

Bacterial infections continue to threaten humankind and the rapid spread of antibiotic resistant bacteria is alarming. Current antibiotics target essential bacterial processes and thereby apply a strong selective pressure on pathogenic and non-pathogenic bacteria alike. One alternative strategy is to block bacterial virulence systems that are essential for the ability to cause disease but not for general bacterial viability. We have previously show that the plant natural product (-)-hopeaphenol blocks the type III secretion system (T3SS) in the Gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa. (-)-Hopeaphenol is a resveratrol tetramer and in the present study we explore various resveratrol dimers, including partial structures of (-)-hopeaphenol, as T3SS inhibitors. To allow rapid and efficient assessment of T3SS inhibition in P. aeruginosa, we developed a new screening method by using a green fluorescent protein reporter under the control of the ExoS promoter. Using a panel of assays we showed that compounds with a benzofuran core structure i.e. viniferifuran, dehydroampelopsin B, anigopreissin A, dehydro-δ-viniferin and resveratrol-piceatannol hybrid displayed significant to moderate activities towards the T3SS in Y. pseudotuberculosis and P. aeruginosa.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-170715 (URN)10.1038/s41598-020-58872-0 (DOI)000560367500001 ()32034212 (PubMedID)2-s2.0-85079083122 (Scopus ID)
Available from: 2020-05-13 Created: 2020-05-13 Last updated: 2023-03-24Bibliographically approved
Projects
Chemical attenuation of bacterial virulence: Inhibitors of type III secretion [2009-02938_VR]; Umeå UniversityUsing Small Molecules to Study Big Questions in Microbiology [2010-04746_VR]; Umeå UniversityChemical attenuation of bacterial virulence - Inhibitors of type III secretion [2012-02802_VR]; Umeå UniversityNya anti-infektiva terapier mot tuberkolos (Beviljad ansökan överförd från Vinnova med dnr 2013-02030) [2013-08775_VR]; Umeå UniversitySmall molecules answer big questions in microbiology [2014-04670_VR]; Umeå UniversityDevelopment of orally bioavailable antibacterials to treat Chlamydia infections [2018-05886_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3219-4669

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