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Lindgren, Cecilia
Publications (10 of 13) Show all publications
Tükenmez, H., Singh, P., Sarkar, S., Çakır, M., Oliveira, A. H., Lindgren, C., . . . Johansson, J. (2023). A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes [Letter to the editor]. mBio, 14(3), Article ID e0044923.
Open this publication in new window or tab >>A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes
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2023 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 3, article id e0044923Article in journal, Letter (Refereed) Published
Abstract [en]

Listeria monocytogenes is a facultative Gram-positive bacterium that causes listeriosis, a severe foodborne disease. We previously discovered that ring-fused 2-pyridone compounds can decrease virulence factor expression in Listeria by binding and inactivating the PrfA virulence activator. In this study, we tested PS900, a highly substituted 2-pyridone that was recently discovered to be bactericidal to other Gram-positive pathogenic bacteria, such as Staphylococcus aureus and Enterococcus faecalis. We show that PS900 can interact with PrfA and reduce the expression of virulence factors. Unlike previous ring-fused 2-pyridones shown to inactivate PrfA, PS900 had an additional antibacterial activity and was found to potentiate sensitivity toward cholic acid. Two PS900-tolerant mutants able to grow in the presence of PS900 carried mutations in the brtA gene, encoding the BrtA repressor. In wild-type (WT) bacteria, cholic acid binds and inactivates BrtA, thereby alleviating the expression of the multidrug transporter MdrT. Interestingly, we found that PS900 also binds to BrtA and that this interaction causes BrtA to dissociate from its binding site in front of the mdrT gene. In addition, we observed that PS900 potentiated the effect of different osmolytes. We suggest that the increased potency of cholic acid and osmolytes to kill bacteria in the presence of PS900 is due to the ability of the latter to inhibit general efflux, through a yet-unknown mechanism. Our data indicate that thiazolino 2-pyridones constitute an attractive scaffold when designing new types of antibacterial agents.

IMPORTANCE: Bacteria resistant to one or several antibiotics are a very large problem, threatening not only treatment of infections but also surgery and cancer treatments. Thus, new types of antibacterial drugs are desperately needed. In this work, we show that a new generation of substituted ring-fused 2-pyridones not only inhibit Listeria monocytogenes virulence gene expression, presumably by inactivating the PrfA virulence regulator, but also potentiate the bactericidal effects of cholic acid and different osmolytes. We identified a multidrug repressor as a second target of 2-pyridones. The repressor–2-pyridone interaction displaces the repressor from DNA, thus increasing the expression of a multidrug transporter. In addition, our data suggest that the new class of ring-fused 2-pyridones are efficient efflux inhibitors, possibly explaining why the simultaneous addition of 2-pyridones together with cholic acid or osmolytes is detrimental for the bacterium. This work proves conclusively that 2-pyridones constitute a promising scaffold to build on for future antibacterial drug design.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
2-pyridones, BrtA, Listeria monocytogenes, PrfA, antibacterial, antibiotic
National Category
Biochemistry and Molecular Biology Microbiology in the medical area Organic Chemistry
Research subject
molecular cell biology
Identifiers
urn:nbn:se:umu:diva-214132 (URN)10.1128/mbio.00449-23 (DOI)000975886700001 ()37120759 (PubMedID)2-s2.0-85172894238 (Scopus ID)
Funder
Familjen Erling-Perssons StiftelseNIH (National Institutes of Health), RO1AI134847-01A1NIH (National Institutes of Health), 1IU19AI157797-01Olle Engkvists stiftelseVinnova, 2019-05491Swedish Research Council, 2020-02005Swedish Research Council, 2018-04589Swedish Research Council, 202105040J
Available from: 2023-09-05 Created: 2023-09-05 Last updated: 2023-10-13Bibliographically approved
Vidal-Albalat, A., Kindahl, T., Rajeshwari, R., Lindgren, C., Forsgren, N., Kitur, S., . . . Linusson, A. (2023). Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes. Journal of Medicinal Chemistry, 66(9), 6333-6353
Open this publication in new window or tab >>Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes
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2023 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 9, p. 6333-6353Article in journal (Refereed) Published
Abstract [en]

Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-208264 (URN)10.1021/acs.jmedchem.3c00234 (DOI)000979350900001 ()37094110 (PubMedID)2-s2.0-85156231351 (Scopus ID)
Funder
Swedish Research Council, 2017-00664The Kempe Foundations
Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-09-05Bibliographically approved
Stael, S., Sabljić, I., Audenaert, D., Andersson, T., Tsiatsiani, L., Kumpf, R. P., . . . Van Breusegem, F. (2023). Structure-function study of a Ca2+-independent metacaspase involved in lateral root emergence. Proceedings of the National Academy of Sciences of the United States of America, 120(22), Article ID e2303480120.
Open this publication in new window or tab >>Structure-function study of a Ca2+-independent metacaspase involved in lateral root emergence
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2023 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 22, article id e2303480120Article in journal (Refereed) Published
Abstract [en]

Metacaspases are part of an evolutionarily broad family of multifunctional cysteine proteases, involved in disease and normal development. As the structure-function relationship of metacaspases remains poorly understood, we solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) belonging to a particular subgroup not requiring calcium ions for activation. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors and found several hits with a minimal thioxodihydropyrimidine-dione structure, of which some are specific AtMCA-IIf inhibitors. We provide mechanistic insight into the basis of inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) effectively hampered lateral root emergence in vivo, probably through inhibition of metacaspases specifically expressed in the endodermal cells overlying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in other species, such as important human pathogens, including those causing neglected diseases.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences (PNAS), 2023
Keywords
AtMCA-IIf crystal structure, cysteine protease, lateral root development, metacaspase, small chemical inhibitor
National Category
Plant Biotechnology
Identifiers
urn:nbn:se:umu:diva-210280 (URN)10.1073/pnas.2303480120 (DOI)37216519 (PubMedID)2-s2.0-85159833521 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2018.0026Knut and Alice Wallenberg Foundation, 2021.0071
Available from: 2023-06-21 Created: 2023-06-21 Last updated: 2023-06-21Bibliographically approved
Lindgren, C., Forsgren, N., Hoster, N., Akfur, C., Artursson, E., Edvinsson, L., . . . Linusson, A. (2022). Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase. Chemistry - A European Journal, 28(40), Article ID e202200678.
Open this publication in new window or tab >>Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase
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2022 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 40, article id e202200678Article in journal (Refereed) Published
Abstract [en]

Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
drug design, kinetics, nerve agent antidotes, reaction mechanisms, structural biology
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-196525 (URN)10.1002/chem.202200678 (DOI)000807066300001 ()35420233 (PubMedID)2-s2.0-85131325691 (Scopus ID)
Funder
Swedish Research Council, 2018-07152Swedish Research Council Formas, 2019-02496Swedish Research Council, 2018-05176
Available from: 2022-06-14 Created: 2022-06-14 Last updated: 2023-03-24Bibliographically approved
Lindgren, C., Tyagi, M., Viljanen, J., Toms, J., Ge, C., Zhang, N., . . . Linusson, A. (2018). Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis. Journal of Medicinal Chemistry, 61(11), 4774-4790
Open this publication in new window or tab >>Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 11, p. 4774-4790Article in journal (Refereed) Published
Abstract [en]

Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-150782 (URN)10.1021/acs.jmedchem.7b01880 (DOI)000435613100008 ()29727183 (PubMedID)2-s2.0-85046659349 (Scopus ID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2023-03-24Bibliographically approved
Knutsson, S., Engdahl, C., Kumari, R., Forsgren, N., Lindgren, C., Kindahl, T., . . . Linusson, A. (2018). Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency. Journal of Medicinal Chemistry, 61(23), 10545-10557
Open this publication in new window or tab >>Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 23, p. 10545-10557Article in journal (Refereed) Published
Abstract [en]

Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-154812 (URN)10.1021/acs.jmedchem.8b01060 (DOI)000453488200014 ()30339371 (PubMedID)2-s2.0-85058504373 (Scopus ID)
Funder
Swedish Research Council, 2014-4218Swedish Research Council, 2014-2636
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2023-03-23Bibliographically approved
Lindgren, C. (2017). Design strategies for new drugs targeting multicomponent systems: focusing on class II MHC proteins and acetylcholinesterase. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Design strategies for new drugs targeting multicomponent systems: focusing on class II MHC proteins and acetylcholinesterase
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Strategier för utveckling av nya läkemedel mot multikomponentsystem : fokus på klass II MHC proteiner och acetylkolinesteras
Abstract [en]

The field of medicinal chemistry is constantly evolving. Aided by advances within techniques as well as knowledge of biological systems, increasingly complex targets and drugs can be considered. This thesis includes two projects focusing on the design of drugs targeting multicomponent systems, referring to systems for which multiple components must be considered during the drug design process.

In the first project, the long-term goal is to develop a vaccine against the autoimmune disease rheumatoid arthritis (RA). The cause of RA is unknown, but it is genetically linked to expression of class II MHC proteins that present antigens to T-cell receptors (TCRs), responsible for initiating an immune response. A glycopeptide fragment, CII259–273, from type II collagen has shown promising results as a vaccine against arthritis resembling RA in mice. CII259–273 binds to the class II MHC protein followed by presentation to the TCR, forming a multicomponent system.

We have used molecular dynamics (MD) simulations to study the effect that modifications of CII259–273 have on the multicomponent system. Non-native amino acids and amide bond isosteres have been introduced. This has demonstrated the importance of retaining the backbone conformation of CII259–273, as well as the hydrogen bonds formed to the backbone. The ability to introduce such modifications would be of value to affect the potency towards the MHC protein, and prevent degradation of the glycopeptide. The studies have revealed a multicomponent system that is highly sensitive to even small modifications that can affect the dynamics of the entire complex.

In the second project, the long-term goal is to develop a broad-spectrum antidote against nerve agents. Nerve agents are extremely toxic compounds that act by covalently inhibiting the enzyme acetylcholinesterase (AChE), which is essential for termination of nerve signalling. A major limitation of current antidotes is that their efficiency is dependent on the type of nerve agent. A broad-spectrum antidote must be able to bind to the multicomponent system consisting of AChE covalently inhibited by different nerve agents. It will then act by performing a nucleophilic attack on the nerve agent adduct, thus breaking the covalent bond to AChE.

We have used statistical molecular design (SMD) and quantitative structure-activity relationship (QSAR) modelling to identify a fragment with a potency for AChE inhibited by different nerve agents. A nucleophilic component able to restore the enzyme to the active form was thereafter introduced. This resulted in a functional reactivator, efficient for multiple nerve agents. Furthermore, the mechanism of reactivation has been investigated through structural studies, enabled by a combination of X-ray crystallography and molecular modelling. A high flexibility of the reactivator, as well as the ability to bind to AChE in multiple conformations, are defined as important properties for a broad-spectrum antidote.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. p. 92
Keywords
acetylcholinesterase, class II MHC protein, drug design, molecular dynamics simulation, multicomponent system, nerve agent, oxime, (quantitative) structure-activity relationship, reactivator, rheumatoid arthritis, statistical molecular design, T-cell receptor
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-137593 (URN)978-91-7601-737-1 (ISBN)
Public defence
2017-09-08, KB.E3.03 (stora hörsalen), KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2017-08-18 Created: 2017-08-14 Last updated: 2018-06-09Bibliographically approved
Andersson, C. D., Hillgren, J. M., Lindgren, C., Qian, W., Akfur, C., Berg, L., . . . Linusson, A. (2015). Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase. Journal of Computer-Aided Molecular Design, 29(3), 199-215
Open this publication in new window or tab >>Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase
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2015 (English)In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 3, p. 199-215Article in journal (Refereed) Published
Abstract [en]

Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

Keywords
Acetylcholinesterase, AChE, Quantitative structure-activity relationship, QSAR, Statistical molecular sign, SMD, Covariance matrix, Descriptors, Correlation
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-101389 (URN)10.1007/s10822-014-9808-1 (DOI)000349888300001 ()25351962 (PubMedID)2-s2.0-84961197150 (Scopus ID)
Available from: 2015-07-07 Created: 2015-03-30 Last updated: 2023-03-23Bibliographically approved
Lindgren, C., Andersson, I. E., Berg, L., Dobritzsch, D., Ge, C., Haag, S., . . . Linusson, A. (2015). Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes. Organic and biomolecular chemistry, 13(22), 6203-6216
Open this publication in new window or tab >>Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes
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2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 22, p. 6203-6216Article in journal (Refereed) Published
Abstract [en]

Class II major histocompatibility complex (MHC) proteins are involved in initiation of immune responses to foreign antigens via presentation of peptides to receptors of CD4(+) T-cells. An analogous presentation of self-peptides may lead to autoimmune diseases, such as rheumatoid arthritis (RA). The glycopeptide fragment CII259-273, derived from type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of collagen induced arthritis (CIA), a validated model for RA. We have introduced hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273. Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified glycopeptides, although static models predicted similar binding modes as the native type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the hydroxyethylene isosteres disturbed the entire hydrogen bond network between the glycopeptides and A(q). As a consequence the hydroxyethylene isosteric glycopeptides were prone to dissociation from A(q) and unfolding of the beta(1)-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-106519 (URN)10.1039/c5ob00395d (DOI)000355489600011 ()25960177 (PubMedID)2-s2.0-84930629552 (Scopus ID)
Available from: 2015-07-15 Created: 2015-07-14 Last updated: 2023-03-23Bibliographically approved
Lindgren, C., Forsgren, N., Akfur, C., Berg, L., Andersson, D., Hillgren, M., . . . Linusson, A.Design of Reactive Drugs: Structure and Mechanism of Novel Nerve Agent Antidotes.
Open this publication in new window or tab >>Design of Reactive Drugs: Structure and Mechanism of Novel Nerve Agent Antidotes
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(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-137590 (URN)
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2018-06-09
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