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Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity
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 Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
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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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 22, p. 9393-9399Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC50 ≤ 20 nM).

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017. Vol. 60, no 22, p. 9393-9399
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-142974DOI: 10.1021/acs.jmedchem.7b00716ISI: 000416500200019PubMedID: 29053275OAI: oai:DiVA.org:umu-142974DiVA, id: diva2:1165876
Available from: 2017-12-14 Created: 2017-12-14 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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Good, James A. D.Kulén, MartinaSilver, JimKrishnan, K. SyamBahnan, WaelNúñez-Otero, CarlosNilsson, IngelaWede, EmmaGylfe, ÅsaBergström, SvenAlmqvist, Fredrik

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Good, James A. D.Kulén, MartinaSilver, JimKrishnan, K. SyamBahnan, WaelNúñez-Otero, CarlosNilsson, IngelaWede, EmmaGylfe, ÅsaBergström, SvenAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Science and Technology)Molecular Infection Medicine Sweden (MIMS)Department of Clinical Microbiology
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Journal of Medicinal Chemistry
Medicinal Chemistry

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