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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
Singh, P., Adolfsson, D. E., Ådén, J., Cairns, A. G., Bartens, C., Brännström, K., . . . Almqvist, F. (2019). Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding. Journal of Organic Chemistry, 84(7), 3887-3903
Open this publication in new window or tab >>Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
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2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed) Published
Abstract [en]

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157464 (URN)10.1021/acs.joc.8b03015 (DOI)000464250800014 ()30862161 (PubMedID)
Funder
Swedish Research Council, 2014-04673Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031The Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-06-13Bibliographically approved
Vain, T., Raggi, S., Ferro, N., Barange, D. K., Kieffer, M., Ma, Q., . . . Robert, S. (2019). Selective auxin agonists induce specific AUX/IAA protein degradation to modulate plant development. Proceedings of the National Academy of Sciences of the United States of America, 116(13), 6463-6472
Open this publication in new window or tab >>Selective auxin agonists induce specific AUX/IAA protein degradation to modulate plant development
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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 13, p. 6463-6472Article in journal (Refereed) Published
Abstract [en]

The plant hormone auxin coordinates almost all aspects of plant development. Throughout plant life, the expression of hundreds of genes involved in auxin regulation is orchestrated via several combinatorial and cell-specific auxin perception systems. An effective approach to dissect these complex pathways is the use of synthetic molecules that target specific processes of auxin activity. Here, we describe synthetic auxins, RubNeddins (RNs), which act as selective auxin agonists. The RN with the greatest potential for dissecting auxin perception was RN4, which we used to reveal a role for the chromatin remodeling ATPase BRAHMA in apical hook development. Therefore, the understanding of RN mode of action paves the way to dissecting specific molecular components involved in auxin-regulated developmental processes.Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCFTIR1/AFB functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1). Here, we report a chemical biology screen that identifies small molecules requiring AXR1 to modulate plant development. We selected four molecules of interest, RubNeddin 1 to 4 (RN1 to -4), among which RN3 and RN4 trigger selective auxin responses at transcriptional, biochemical, and morphological levels. This selective activity is explained by their ability to consistently promote the interaction between TIR1 and a specific subset of AUX/IAA proteins, stimulating the degradation of particular AUX/IAA combinations. Finally, we performed a genetic screen using RN4, the RN with the greatest potential for dissecting auxin perception, which revealed that the chromatin remodeling ATPase BRAHMA is implicated in auxin-mediated apical hook development. These results demonstrate the power of selective auxin agonists to dissect auxin perception for plant developmental functions, as well as offering opportunities to discover new molecular players involved in auxin responses.

Place, publisher, year, edition, pages
Washington: Proceedings of the National Academy of Sciences of the United States of America (PNAS), 2019
Keywords
auxin, chemical biology, selective agonist, prohormone, hormone perception
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-157293 (URN)10.1073/pnas.1809037116 (DOI)000462382800094 ()30850516 (PubMedID)
Funder
Swedish Research Council, 2013-4632Swedish Research Council, 2016-00768VinnovaKnut and Alice Wallenberg FoundationStiftelsen Olle Engkvist ByggmästareThe Kempe FoundationsCarl Tryggers foundation NIH (National Institute of Health), NIH GM43644
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-04-12Bibliographically approved
Singh, P., Cairns, A. G., Adolfsson, D. E., Ådén, J., Sauer, U. H. & Almqvist, F. (2019). Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones. Organic Letters
Open this publication in new window or tab >>Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones
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2019 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052Article in journal (Refereed) Epub ahead of print
Abstract [en]

We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry Inorganic Chemistry Polymer Chemistry
Identifiers
urn:nbn:se:umu:diva-162826 (URN)10.1021/acs.orglett.9b02549 (DOI)31419146 (PubMedID)
Available from: 2019-08-30 Created: 2019-08-30 Last updated: 2019-09-03
Olsen, L. K., Cairns, A. G., Ådén, J., Moriarty, N., Cabre, S., Alamilla, V. R., . . . McKernan, D. P. (2019). Viral mimetic priming enhances α-synuclein-induced degeneration: implications for Parkinson's disease. Brain, behavior, and immunity, 80, 525-535
Open this publication in new window or tab >>Viral mimetic priming enhances α-synuclein-induced degeneration: implications for Parkinson's disease
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2019 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 80, p. 525-535Article in journal (Refereed) Published
Abstract [en]

Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson’s disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson’s disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson’s disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson’s disease.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Parkinson’s disease, Viral infection, Neuroinflammation, α-Synuclein, Neurodegeneration
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-159474 (URN)10.1016/j.bbi.2019.04.036 (DOI)000478105500051 ()31029796 (PubMedID)
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-09-10Bibliographically approved
Petzold, D., Singh, P., Almqvist, F. & König, B. (2019). Visible light mediated synthesis of β chloro ketones from aryl cyclopropanes. Angewandte Chemie International Edition, 58, 8577-8580
Open this publication in new window or tab >>Visible light mediated synthesis of β chloro ketones from aryl cyclopropanes
2019 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, p. 8577-8580Article in journal (Refereed) Published
Abstract [en]

We report the visible light mediated synthesis of β chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid and nitric acid. The operationally simple and catalyst free method uses cheap standard lab reagents and displays a broad functional group tolerance. Moreover, scale up of the reaction and late stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked β chloro ketone in a reaction sequence. We propose a light‐driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid producing small quantities of molecular chlorine. The mechanistic hypothesis is supported by 18O labelling and UV‐VIS experiments, cyclovoltammetry and several control reactions.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
photochemistry, aryl cyclopropane, β chloro ketone, radical chain reaction, late-stage modification
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157629 (URN)10.1002/anie.201902473 (DOI)000476608700052 ()30901148 (PubMedID)
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-09-09Bibliographically approved
Cairns, A. G., Vazquez-Romero, A., Mahdi-Moein, M., Ådén, J., Elmore, C. S., Takano, A., . . . Schou, M. (2018). Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy [Letter to the editor]. ACS Chemical Neuroscience, 9(11), 2542-2547
Open this publication in new window or tab >>Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
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2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 11, p. 2542-2547Article in journal, Letter (Refereed) Published
Abstract [en]

Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Alpha-synuclein, carbon-11, PET
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-151139 (URN)10.1021/acschemneuro.8b00236 (DOI)000451496200005 ()29901990 (PubMedID)
Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2018-12-19Bibliographically approved
Omattage, N. S., Deng, Z., Pinkner, J. S., Dodson, K. W., Almqvist, F., Yuan, P. & Hultgren, S. J. (2018). Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli [Letter to the editor]. Nature Microbiology, 3(12), 1362-1368
Open this publication in new window or tab >>Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli
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2018 (English)In: Nature Microbiology, E-ISSN 2058-5276, Vol. 3, no 12, p. 1362-1368Article in journal, Letter (Refereed) Published
Abstract [en]

Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases(1). During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane beta-barrel translocation domain, a beta-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2)(2-6). Despite extensive structural and functional characterization, the mechanism by which the usher is activated to initiate pilus biogenesis is unknown. Here, we present the crystal structure of the full-length PapC usher from Escherichia coli in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state, elucidating molecular details of how the usher is specifically engaged by allosteric interactions with its substrate preceding activation and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly. This work elucidates the intricate workings of a molecular machine that catalyses chaperone-usher pathway pilus assembly and opens the door for the development of potent inhibitors to block pilus biogenesis.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-154340 (URN)10.1038/s41564-018-0255-y (DOI)000451259600009 ()30275511 (PubMedID)
Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2018-12-18Bibliographically approved
Kulén, M., Lindgren, M., Hansen, S., Cairns, A. G., Grundström, C., Begum, A., . . . Almqvist, F. (2018). Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes. Journal of Medicinal Chemistry, 61(9), 4165-4175
Open this publication in new window or tab >>Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 9, p. 4165-4175Article in journal (Refereed) Published
Abstract [en]

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-148830 (URN)10.1021/acs.jmedchem.8b00289 (DOI)000432204800027 ()29667825 (PubMedID)2-s2.0-85046422455 (Scopus ID)
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-08-28Bibliographically approved
Wixe, T. & Almqvist, F. (2017). An improved synthesis of 3-[1-(trifluoromethy1)-3H-1,2-diazirin-3-yl] aniline: a key intermediate in the synthesis of photoaffinity probes. Tetrahedron Letters, 58(34), 3350-3352
Open this publication in new window or tab >>An improved synthesis of 3-[1-(trifluoromethy1)-3H-1,2-diazirin-3-yl] aniline: a key intermediate in the synthesis of photoaffinity probes
2017 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 58, no 34, p. 3350-3352Article in journal (Refereed) Published
Abstract [en]

An improved synthesis of 3-[3-(trifluoromethyl)-3H-1,2-diazirin-3-yflaniline, achieving an overall yield of 38% over seven steps is reported. Only three chromatographic separations were needed and the preparation of similar to 0.7 g of the target compound was demonstrated. The stability of the diazirine in solution at room temperature while exposed to ambient light was studied. No significant degradation of the compound was observed over the course of five weeks in a 130 mM sample and only minor degradation was observed in weaker samples (10, 5, and 2.5 mM), as demonstrated by H-1 and F-19 NMR.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Diazirine, Preparative synthesis, Photolysis, Stability
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-139141 (URN)10.1016/j.tetlet.2017.07.031 (DOI)000407657600005 ()
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-06-09Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-4646-0216

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