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Unnatural Endotype B PPAPs as Novel Compounds with Activity against Mycobacterium tuberculosis
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    Unnatural Endotype B PPAPs as Novel Compounds with Activity against Mycobacterium tuberculosis
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    • Philipp Peslalz
      Philipp Peslalz
      Chair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,Germany
    • Mark Grieshober
      Mark Grieshober
      Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Albert-Einstein-Allee 11, Ulm D-89081, Germany
    • Frank Kraus
      Frank Kraus
      Institut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, Germany
      More by Frank Kraus
    • Anton Bleisch
      Anton Bleisch
      Chair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,Germany
    • Flavia Izzo
      Flavia Izzo
      Institut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, Germany
      More by Flavia Izzo
    • Dajana Lichtenstein
      Dajana Lichtenstein
      Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, Germany
    • Helen Hammer
      Helen Hammer
      SIGNATOPE GmbH, Markwiesenstr. 55, Reutlingen 72770, Germany
      More by Helen Hammer
    • Andreas Vorbach
      Andreas Vorbach
      Interfaculty Institute of Microbiology and Infection Medicine, Tübingen 72076, Germany
    • Kyoko Momoi
      Kyoko Momoi
      Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Auerbachstr. 112, University of Tübingen, 70376 Stuttgart, Tübingen 72076, Germany
      More by Kyoko Momoi
    • Ulrich M. Zanger
      Ulrich M. Zanger
      Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Auerbachstr. 112, University of Tübingen, 70376 Stuttgart, Tübingen 72076, Germany
    • Heike Brötz-Oesterhelt
      Heike Brötz-Oesterhelt
      Interfaculty Institute of Microbiology and Infection Medicine, Tübingen 72076, Germany
      German Center for Infection Research, Partner Site Tübingen, Tübingen 72076, Germany
    • Albert Braeuning
      Albert Braeuning
      Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, Germany
    • Bernd Plietker*
      Bernd Plietker
      Chair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,Germany
      Institut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, Germany
      *Email: [email protected]
    • Steffen Stenger*
      Steffen Stenger
      Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Albert-Einstein-Allee 11, Ulm D-89081, Germany
      *Email: steffen.stenger@[email protected]
    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 22, 15073–15083
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    https://doi.org/10.1021/acs.jmedchem.3c01172
    Published October 12, 2023
    Copyright © 2023 The Authors. Published by American Chemical Society

    Abstract

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    Pre-SARS-CoV-2, tuberculosis was the leading cause of death by a single pathogen. Repetitive exposure of Mycobacterium tuberculosis(Mtb) supported the development of multidrug- and extensively drug-resistant strains, demanding novel drugs. Hyperforin, a natural type A polyprenylated polycyclic acylphloroglucinol from St. John’s wort, exhibits antidepressant and antibacterial effects also against Mtb. Yet, Hyperforin’s instability limits the utility in clinical practice. Here, we present photo- and bench-stable type B PPAPs with enhanced antimycobacterial efficacy. PPAP22 emerged as a lead compound, further improved as the sodium salt PPAP53, drastically enhancing solubility. PPAP53 inhibits the growth of virulent extracellular and intracellular Mtb without harming primary human macrophages. Importantly, PPAP53 is active against drug-resistant strains of Mtb. Furthermore, we analyzed the in vitro properties of PPAP53 in terms of CYP induction and the PXR interaction. Taken together, we introduce type PPAPs as a new class of antimycobacterial compounds, with remarkable antibacterial activity and favorable biophysical properties.

    Copyright © 2023 The Authors. Published by American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01172.

    • Additional synthetic schemes, sequences and qPCR primers, dual-luciferase report assay data on final compounds, and characterization data for target compounds (PDF)

    • Molecular formula strings (CSV)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

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    This article is cited by 3 publications.

    1. Lihong Liang, Zhiyong Liu, Jie Chen, Qin Zha, Yihuan Zhou, Jun Li, Yangbo Hu, Xinwen Chen, Tianyu Zhang, Niuniu Zhang. Design and synthesis of Thieno[3, 2-b]pyridinone derivatives exhibiting potent activities against Mycobacterium tuberculosis in vivo by targeting Enoyl-ACP reductase. European Journal of Medicinal Chemistry 2024, 279 , 116806. https://doi.org/10.1016/j.ejmech.2024.116806
    2. Philipp Peslalz, Andreas Vorbach, Anton Bleisch, Elisa Liberini, Frank Kraus, Flavia Izzo, Heike Brötz‐Oesterhelt, Friedrich Götz, Bernd Plietker. Chemical Predictive Modelling and Natural Product‐based Divergent Synthesis – Design of Type B PPAPs with Nanomolar Activities against MRSA. Chemistry – A European Journal 2024, 30 (46) https://doi.org/10.1002/chem.202401955
    3. Aparna Viswanathan Ammanath, Miki Matsuo, Huanhuan Wang, Frank Kraus, Anton Bleisch, Philipp Peslalz, Majd Mohammad, Meghshree Deshmukh, Anne Grießhammer, Moushumi Purkayastha, Andreas Vorbach, Boris Macek, Heike Brötz-Oesterhelt, Lisa Maier, Dorothee Kretschmer, Andreas Peschel, Tao Jin, Bernd Plietker, Friedrich Götz. Antimicrobial Evaluation of Two Polycyclic Polyprenylated Acylphloroglucinol Compounds: PPAP23 and PPAP53. International Journal of Molecular Sciences 2024, 25 (15) , 8023. https://doi.org/10.3390/ijms25158023

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 22, 15073–15083
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.3c01172
    Published October 12, 2023
    Copyright © 2023 The Authors. Published by American Chemical Society

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