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Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
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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. Vol. 61, no 9, p. 4165-4175
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-148830DOI: 10.1021/acs.jmedchem.8b00289ISI: 000432204800027PubMedID: 29667825Scopus ID: 2-s2.0-85046422455OAI: oai:DiVA.org:umu-148830DiVA, id: diva2:1217767
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-08-28Bibliographically approved
In thesis
1. New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
Open this publication in new window or tab >>New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Design, syntes och utvärdering av substituerade ringsammansatta 2-pyridoner med biologisk aktivitet mot Listeria monocytogenes och Chlamydia trachomatis
Abstract [en]

Antibiotic resistance has become a global health burden with the number of resistant bacteria continuously increasing. Antibiotic drugs act by being either bactericidal (killing bacteria) or bacteriostatic (inhibiting growth of bacteria). However, these modes of action increase the selective pressure on the bacteria. An alternative treatment strategy to antibiotics is anti-virulence therapies that inhibits virulence of the pathogenic bacteria. The term “virulence” summarises a number of factors that the bacteria need to colonise a new niche and as a consequence its ability to infect and cause diseases. By inhibiting virulence, instead of killing, the selective pressure on the bacteria can be reduced and consequently decreases the rapid development of resistance. This thesis describes two projects focusing on development of anti-virulence agents, with the ring-fused 2-pyridone scaffold as the central character, targeting the bacteria Listeria monocytogenes and Chlamydia trachomatis.

The first project is targeting L. monocytogenes, which is the cause for listeriosis in humans. This can develop into life-threatening encephalitis and meningitis as well as cause severe complications for developing fetus. The target in L. monocytogenes is the transcriptional regulator PrfA that control almost all virulence factors in this bacterium. We have designed and synthesised potent substituted ring-fused 2-pyridones, which at low micromolar concentrations block activation of the virulence regulator PrfA and thus attenuate the bacterial infection. Co-crystallisation of the active ring-fused 2-pyridones with PrfA resulted in determination of the exact substance interaction site in the protein. This facilitated further structure-based design that resulted in improved compounds capable of attenuating L. monocytogenes in an in vivo model.

The second project targets C. trachomatis, which is the causative agent behind the most common sexually transmitted infection as well as the eye infection trachoma. By structure-activity relationship analysis of previously tested ring-fused 2-pyridones, we have designed and synthesised non-hydrolysable ring-fused 2-pyridone amide isosteres. The most potent analogues inhibit C. trachomatis infectivity at low nanomolar concentrations, without showing host cell toxicity or affecting the viability of commensal microbiota. Introduction of heteroatom substituents at specific sites of the ring-fused 2-pyridone scaffold, resulted in improved pharmacokinetic properties of the analogues and further evaluation in vivo was performed.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2018. p. 86
Keywords
Antibiotic resistance, anti-virulence, Listeria monocytogenes, Chlamydia trachomatis, ring-fused 2-pyridone, organic synthesis, structure-based design, PrfA, drug design, structure-activity relationship
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-151128 (URN)978-91-7601-920-7 (ISBN)
Public defence
2018-09-21, KB.E3.03 (Stora hörsalen), KBC-huset, Umeå, 09:00 (English)
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Available from: 2018-08-31 Created: 2018-08-28 Last updated: 2018-08-29Bibliographically approved

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Kulén, MartinaLindgren, MarieHansen, SabineCairns, Andrew G.Grundström, ChristinBegum, Afshanvan der Lingen, IngeborgBrännström, KristofferHall, MichaelSauer, Uwe H.Johansson, JörgenSauer-Eriksson, A. ElisabethAlmqvist, Fredrik

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Kulén, MartinaLindgren, MarieHansen, SabineCairns, Andrew G.Grundström, ChristinBegum, Afshanvan der Lingen, IngeborgBrännström, KristofferHall, MichaelSauer, Uwe H.Johansson, JörgenSauer-Eriksson, A. ElisabethAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Clinical BacteriologyDepartment of Molecular Biology (Faculty of Medicine)Molecular Infection Medicine Sweden (MIMS)Department of Medical Biochemistry and Biophysics
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Journal of Medicinal Chemistry
Medicinal Chemistry

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