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Bengtsson, Christoffer
Publications (10 of 14) Show all publications
Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., . . . Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517
Open this publication in new window or tab >>Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Place, publisher, year, edition, pages
The National Academy of Scionces of the United States of America, 2019
Keywords
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-159857 (URN)10.1073/pnas.1818009116 (DOI)000468403400054 ()31061116 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research The Kempe FoundationsNIH (National Institute of Health)
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Bengtsson, C., Nelander, H. & Almqvist, F. (2013). Asymmetric Synthesis of 2,4,5-Trisubstituted (2)-Thiazolines. Chemistry - A European Journal, 19(30), 9916-9922
Open this publication in new window or tab >>Asymmetric Synthesis of 2,4,5-Trisubstituted (2)-Thiazolines
2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 30, p. 9916-9922Article in journal (Refereed) Published
Abstract [en]

(2)-Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5-trisubstituted (2)-thiazolines. These (2)-thiazolines were synthesized from readily accessible/commercially available ,-unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an ON acyl migration reaction as key steps. The final products were obtained in good yields with up to 97% enantiomeric excess.

Keywords
acyl migration, asymmetric synthesis, heterocycles, unnatural amino acids, thiazolines
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-79422 (URN)10.1002/chem.201301120 (DOI)000321766400029 ()
Available from: 2013-09-04 Created: 2013-08-19 Last updated: 2018-06-08Bibliographically approved
Andersson, E. K., Bengtsson, C., Evans, M. L., Chorell, E., Sellstedt, M., Lindgren, A. E. .., . . . Chapman, M. R. (2013). Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones. Chemistry and Biology, 20(10), 1245-1254
Open this publication in new window or tab >>Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones
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2013 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 20, no 10, p. 1245-1254Article in journal (Refereed) Published
Abstract [en]

Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."

Place, publisher, year, edition, pages
Elsevier, 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-82340 (URN)10.1016/j.chembiol.2013.07.017 (DOI)000326429400010 ()24035282 (PubMedID)
Funder
Swedish Research Council, 2011-6259, 2010-4730
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2018-06-08Bibliographically approved
Bengtsson, C. (2013). Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections.

Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent.

The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.   

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. p. 85
Keywords
Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial
National Category
Natural Sciences
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-68709 (URN)978-91-7459-552-9 (ISBN)
Public defence
2013-05-24, KBC-Huset, KB3B1, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2013-05-03 Created: 2013-04-23 Last updated: 2018-06-08Bibliographically approved
Chorell, E., Pinkner, J. S., Bengtsson, C., Edvinsson, S., Cusumano, C. K., Rosenbaum, E., . . . Almqvist, F. (2012). Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms. Chemistry - A European Journal, 18(15), 4522-4532
Open this publication in new window or tab >>Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms
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2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, p. 4522-4532Article in journal (Refereed) Published
Abstract [en]

Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.

Place, publisher, year, edition, pages
Berlin: Wiley-VCH Verlagsgesellschaft, 2012
Keywords
antivirulence, biological activity, coumarin, fluorescence, structure–activity relationships
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-53543 (URN)10.1002/chem.201103936 (DOI)22431310 (PubMedID)
Available from: 2012-04-02 Created: 2012-04-02 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
Chorell, E., Pinkner, J. S., Bengtsson, C., Banchelin, T.-L. S., Edvinsson, S., Linusson, A., . . . Almqvist, F. (2012). Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study. Bioorganic & Medicinal Chemistry, 20(9), 3128-3142
Open this publication in new window or tab >>Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study
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2012 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 20, no 9, p. 3128-3142Article in journal (Refereed) Published
Abstract [en]

Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC(50) of 400nM.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Synechocystis-sp PCC-6803, CAB-like proteins, Alga Chlamydomonas-ReinhardTII, Pigment-Binding Protein, Plant Photosystem-I, State Transitions, Arabidopsis-Thaliana, Antenna Proteins, Gene Family, Inducible Protein
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-54385 (URN)10.1016/j.bmc.2012.01.048 (DOI)000303002100040 ()22464688 (PubMedID)
Available from: 2012-04-25 Created: 2012-04-25 Last updated: 2018-06-08Bibliographically approved
Horvath, I., Weise, C. F., Andersson, E. K., Chorell, E., Sellstedt, M., Bengtsson, C., . . . Wittung-Stafshede, P. (2012). Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation. Journal of the American Chemical Society, 134(7), 3439-3444
Open this publication in new window or tab >>Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation
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2012 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 7, p. 3439-3444Article in journal (Refereed) Published
Abstract [en]

Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human α-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates α-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled α-synuclein show that upon FN075 addition, α-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain β-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for α-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-52526 (URN)10.1021/ja209829m (DOI)22260746 (PubMedID)
Available from: 2012-02-24 Created: 2012-02-24 Last updated: 2018-06-08Bibliographically approved
Bengtsson, C. & Almqvist, F. (2011). A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds. Journal of Organic Chemistry, 76(23), 9817-9825
Open this publication in new window or tab >>A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds
2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 23, p. 9817-9825Article in journal (Refereed) Published
Abstract [en]

Ringfused bicyclic 2-pyridones exhibit interesting biological properties against pili assembly in uropathogenic E. coli1 as well as curli formation2. In the strive for new ring-fused central fragments highly selective synthetic routes to the 2-furanone or 2-pyrone containing tricyclic scaffolds 1 and 2 have been developed.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-49167 (URN)10.1021/jo201952p (DOI)22008034 (PubMedID)
Available from: 2011-11-01 Created: 2011-11-01 Last updated: 2018-06-08Bibliographically approved
Chorell, E., Bengtsson, C., Sainte-Luce Banchelin, T., Das, P., Uvell, H., Sinha, A. K., . . . Almqvist, F. (2011). Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity. European Journal of Medicinal Chemistry, 46(4), 1103-1116
Open this publication in new window or tab >>Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
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2011 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, no 4, p. 1103-1116Article in journal (Refereed) Published
Abstract [en]

Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.

Place, publisher, year, edition, pages
Elsevier Masson SAS, 2011
Keywords
Pilicide, Anti-virulence, 2-Pyridone, peptidomimetic
National Category
Infectious Medicine Organic Chemistry Inorganic Chemistry Medicinal Chemistry Organic Chemistry
Research subject
Biorganic Chemistry; Infectious Diseases; läkemedelskemi; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-43916 (URN)10.1016/j.ejmech.2011.01.025 (DOI)21316127 (PubMedID)
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2018-06-08Bibliographically approved
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