New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents

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Kulén, Martina,1988-Umeå universitet,Kemiska institutionen (författare)

New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis : Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents

BokEngelska2018

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Umeå :Umeå universitet,2018
86 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:umu-151128
ISBN:9789176019207
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-151128URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:dok swepub-publicationtype

Varianttitlar

Design, syntes och utvärdering av substituerade ringsammansatta 2-pyridoner med biologisk aktivitet mot Listeria monocytogenes och Chlamydia trachomatis

Anmärkningar

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.

Ämnesord och genrebeteckningar

NATURVETENSKAP Kemi Organisk kemi hsv//swe
NATURAL SCIENCES Chemical Sciences Organic Chemistry hsv//eng
Antibiotic resistance
anti-virulence
Listeria monocytogenes
Chlamydia trachomatis
ring-fused 2-pyridone
organic synthesis
structure-based design
PrfA
drug design
structure-activity relationship

Biuppslag (personer, institutioner, konferenser, titlar ...)

Almqvist, Fredrik,ProfessorUmeå universitet,Kemiska institutionen(Swepub:umu)fral0001 (preses)
Linusson Jonsson, Anna,Professor,1970-Umeå universitet,Kemiska institutionen(Swepub:umu)analin99 (preses)
Pontén, Fritiof,Dr.QureTech Bio AB(Swepub:umu)frpo0007 (preses)
Strøm, Morten B.,ProfessorDepartment of Pharmacy, University of Tromsø, Tromsø, Norway (opponent)
Umeå universitetKemiska institutionen (creator_code:org_t)

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Av författaren/redakt...: Kulén, Martina, ...; Almqvist, Fredri ...; Linusson Jonsson ...; Pontén, Fritiof, ...; Strøm, Morten B. ...

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NATURVETENSKAP: NATURVETENSKAP; och Kemi; och Organisk kemi

Av lärosätet: Umeå universitet

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