umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)Alternativ titel
Design, syntes och utvärdering av substituerade ringsammansatta 2-pyridoner med biologisk aktivitet mot Listeria monocytogenes och Chlamydia trachomatis (Svenska)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet , 2018. , s. 86
Nyckelord [en]
Antibiotic resistance, anti-virulence, Listeria monocytogenes, Chlamydia trachomatis, ring-fused 2-pyridone, organic synthesis, structure-based design, PrfA, drug design, structure-activity relationship
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-151128ISBN: 978-91-7601-920-7 (tryckt)OAI: oai:DiVA.org:umu-151128DiVA, id: diva2:1242449
Disputation
2018-09-21, KB.E3.03 (Stora hörsalen), KBC-huset, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-08-31 Skapad: 2018-08-28 Senast uppdaterad: 2018-08-29Bibliografiskt granskad
Delarbeten
1. Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
Öppna denna publikation i ny flik eller fönster >>Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
Visa övriga...
2018 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, nr 9, s. 4165-4175Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2018
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:umu:diva-148830 (URN)10.1021/acs.jmedchem.8b00289 (DOI)000432204800027 ()29667825 (PubMedID)2-s2.0-85046422455 (Scopus ID)
Tillgänglig från: 2018-06-13 Skapad: 2018-06-13 Senast uppdaterad: 2018-08-28Bibliografiskt granskad
2. Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity
Öppna denna publikation i ny flik eller fönster >>Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity
Visa övriga...
2017 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, nr 22, s. 9393-9399Artikel i tidskrift (Refereegranskat) 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).

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2017
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:umu:diva-142974 (URN)10.1021/acs.jmedchem.7b00716 (DOI)000416500200019 ()29053275 (PubMedID)
Tillgänglig från: 2017-12-14 Skapad: 2017-12-14 Senast uppdaterad: 2018-08-28Bibliografiskt granskad
3. Design, Synthesis, and Evaluation of Chlamydia trachomatis Infectivity Inhibitors with Improved Pharmacokintetic Properties
Öppna denna publikation i ny flik eller fönster >>Design, Synthesis, and Evaluation of Chlamydia trachomatis Infectivity Inhibitors with Improved Pharmacokintetic Properties
Visa övriga...
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-151127 (URN)
Tillgänglig från: 2018-08-28 Skapad: 2018-08-28 Senast uppdaterad: 2018-08-28

Open Access i DiVA

fulltext(2433 kB)237 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 2433 kBChecksumma SHA-512
651774ed424973dd25e2ac89f8854afa7929ccac9fee94690c6bb28087ab9a5330c9d66b1e5defa927e91c028dc8e2c00f8af65eec788da7eb0a866957d1b395
Typ fulltextMimetyp application/pdf
spikblad(295 kB)13 nedladdningar
Filinformation
Filnamn SPIKBLAD01.pdfFilstorlek 295 kBChecksumma SHA-512
b572870c256442297a46651308a4d422f6393e74b231aa7b726bee6e24672fb62e68cc1543f08ba7337a5a217346969b12e077fdf9ae50099db417a2b5f754cd
Typ spikbladMimetyp application/pdf

Personposter BETA

Kulén, Martina

Sök vidare i DiVA

Av författaren/redaktören
Kulén, Martina
Av organisationen
Kemiska institutionen
Organisk kemi

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 237 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

isbn
urn-nbn

Altmetricpoäng

isbn
urn-nbn
Totalt: 814 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf