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Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Visa övriga samt affilieringar
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. Vol. 60, nr 22, s. 9393-9399
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:umu:diva-142974DOI: 10.1021/acs.jmedchem.7b00716ISI: 000416500200019PubMedID: 29053275OAI: oai:DiVA.org:umu-142974DiVA, id: diva2:1165876
Tillgänglig från: 2017-12-14 Skapad: 2017-12-14 Senast uppdaterad: 2018-08-28Bibliografiskt granskad
Ingår i avhandling
1. New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
Öppna denna publikation i ny flik eller fönster >>New alternatives to combat Listeria monocytogenes and Chlamydia trachomatis: Design, synthesis, and evaluation of substituted ring-fused 2-pyridones as anti-virulent agents
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2018. s. 86
Nyckelord
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:nbn:se:umu:diva-151128 (URN)978-91-7601-920-7 (ISBN)
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

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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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Kemiska institutionenUmeå Centre for Microbial Research (UCMR)Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)Molekylär Infektionsmedicin, Sverige (MIMS)Institutionen för klinisk mikrobiologi
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