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A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2021 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 5, article id e01826-20Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-Pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first-generation compound KSK120 inhibits the developmental cycle of Chlamydia, resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis, and the effect was only observable upon reinfection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen Chlamydia muridarum and in Chlamydia caviae. The molecular target of KSK213 may thus be different in C. trachomatis or nonessential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNase III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-Pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

Place, publisher, year, edition, pages
American Society for Microbiology , 2021. Vol. 65, no 5, article id e01826-20
Keywords [en]
Chlamydia trachomatis, antibacterial agents, intracellular bacteria, mode of action, virulence inhibitors
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-174665DOI: 10.1128/AAC.01826-20ISI: 000641612600035Scopus ID: 2-s2.0-85105036198OAI: oai:DiVA.org:umu-174665DiVA, id: diva2:1462530
Note

Originally included in thesis in manuscript form.

Available from: 2020-08-31 Created: 2020-08-31 Last updated: 2023-09-05Bibliographically approved
In thesis
1. Novel inhibitors of Chlamydia trachomatis virulence
Open this publication in new window or tab >>Novel inhibitors of Chlamydia trachomatis virulence
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2020. p. 48
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2092
Keywords
Chlamydia trachomatis, 2-pyridone, small molecules, KSK213, Structure-Activity Relationships (SAR), antibiotic resistance, target identification, transcription, RNA, progeny, infectivity
National Category
Infectious Medicine Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medicinal Chemistry Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-174666 (URN)978-91-7855-340-2 (ISBN)978-91-7855-339-6 (ISBN)
Public defence
2020-09-25, Triple Helix, University management building, Umeå, 13:00 (English)
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Note

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

Available from: 2020-09-04 Created: 2020-09-01 Last updated: 2020-09-02Bibliographically approved

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Núñez-Otero, CarlosBahnan, WaelVielfort, KatarinaSilver, JimSingh, PardeepElbir, HaithamAlmqvist, FredrikBergström, SvenGylfe, Åsa

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Núñez-Otero, CarlosBahnan, WaelVielfort, KatarinaSilver, JimSingh, PardeepElbir, HaithamAlmqvist, FredrikBergström, SvenGylfe, Åsa
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Department of Clinical MicrobiologyDepartment of Molecular Biology (Faculty of Medicine)Department of Chemistry
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