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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).ORCID-id: 0000-0003-2377-030X
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: 29053275Scopus ID: 2-s2.0-85035335813OAI: oai:DiVA.org:umu-142974DiVA, id: diva2:1165876
Tillgänglig från: 2017-12-14 Skapad: 2017-12-14 Senast uppdaterad: 2023-08-25Bibliografiskt 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
2. Novel inhibitors of Chlamydia trachomatis virulence
Öppna denna publikation i ny flik eller fönster >>Novel inhibitors of Chlamydia trachomatis virulence
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Chlamydia trachomatis is an obligate intracellular bacterium that infects over 100 million people globally every year. Chlamydia infections can be persistent, cause infertility and blindness, adding an economical burden in the healthcare systems. Moreover, Chlamydia infections are treated with broad-spectrum antibiotics that contribute to the selection of antibiotic resistant bacteria in the commensal flora. For this reason, novel compounds with specificity against C. trachomatis would be important for treatment of Chlamydia infections.

We have developed a new class of substituted 2-pyridone amides that inhibited development of C. trachomatis. While bacterial growth was only affected to a limited extent, the produced progeny bacteria had impaired capacity to infect new cells. The compounds presented no toxicity in human or mouse cell lines and they did not inhibit growth of bacteria from the normal flora. Structure activity relationship (SAR) development of 2-pyridones lead to compounds with effect at nanomolar concentrations. Further modifications of the C3 part of the molecules resulted in isostere compounds with even a higher potency. By exploring the C8 position, we observed that methylsulfonamide substituents improved the pharmacokinetic properties and enabled oral uptake in mice. This discovery opens the door for oral treatment.

Among 2-pyridone amides, KSK213 was one of the most potent and we investigated the mode of action on the life cycle of C. trachomatis. KSK213 reduced transcription by the end of the developmental cycle and upon infection of new host cells. Mutations in RNA helicase and RNAse III genes, involved in transcription, mediated resistance to KSK213. It also attenuated the infectivity in a mouse vaginal infection model. To further explore the molecular target for 2-pyridone amides in Chlamydia, we used a custom synthesized probe for affinity chromatography approaches.

Here we show that 2-pyridones are potent non-toxic inhibitors of C. trachomatis that can be chemically modified to increase potency and enable oral bioavailability. These molecules have the potential to treat and prevent Chlamydia infections without affecting the normal flora.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2020. s. 48
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2092
Nyckelord
Chlamydia trachomatis, 2-pyridone, small molecules, KSK213, Structure-Activity Relationships (SAR), antibiotic resistance, target identification, transcription, RNA, progeny, infectivity
Nationell ämneskategori
Infektionsmedicin Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Läkemedelskemi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-174666 (URN)978-91-7855-340-2 (ISBN)978-91-7855-339-6 (ISBN)
Disputation
2020-09-25, Triple Helix, University management building, Umeå, 13:00 (Engelska)
Opponent
Handledare
Anmärkning

Additional appendix only available in printed version, as it contains specific methods that we want to publish in the future. 

Tillgänglig från: 2020-09-04 Skapad: 2020-09-01 Senast uppdaterad: 2020-09-02Bibliografiskt 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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