Unnatural Endotype B PPAPs as Novel Compounds with Activity against Mycobacterium tuberculosisClick to copy article linkArticle link copied!
- Philipp PeslalzPhilipp PeslalzChair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,GermanyMore by Philipp Peslalz
- Mark GrieshoberMark GrieshoberInstitute for Medical Microbiology and Hygiene, University Hospital Ulm, Albert-Einstein-Allee 11, Ulm D-89081, GermanyMore by Mark Grieshober
- Frank KrausFrank KrausInstitut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, GermanyMore by Frank Kraus
- Anton BleischAnton BleischChair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,GermanyMore by Anton Bleisch
- Flavia IzzoFlavia IzzoInstitut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, GermanyMore by Flavia Izzo
- Dajana LichtensteinDajana LichtensteinDepartment of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, GermanyMore by Dajana Lichtenstein
- Helen Hammer
- Andreas VorbachAndreas VorbachInterfaculty Institute of Microbiology and Infection Medicine, Tübingen 72076, GermanyMore by Andreas Vorbach
- Kyoko MomoiKyoko MomoiDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Auerbachstr. 112, University of Tübingen, 70376 Stuttgart, Tübingen 72076, GermanyMore by Kyoko Momoi
- Ulrich M. ZangerUlrich M. ZangerDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Auerbachstr. 112, University of Tübingen, 70376 Stuttgart, Tübingen 72076, GermanyMore by Ulrich M. Zanger
- Heike Brötz-OesterheltHeike Brötz-OesterheltInterfaculty Institute of Microbiology and Infection Medicine, Tübingen 72076, GermanyGerman Center for Infection Research, Partner Site Tübingen, Tübingen 72076, GermanyMore by Heike Brötz-Oesterhelt
- Albert BraeuningAlbert BraeuningDepartment of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, GermanyMore by Albert Braeuning
- Bernd Plietker*Bernd Plietker*Email: [email protected]Chair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,GermanyInstitut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, GermanyMore by Bernd Plietker
- Steffen Stenger*Steffen Stenger*Email: steffen.stenger@[email protected]Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Albert-Einstein-Allee 11, Ulm D-89081, GermanyMore by Steffen Stenger
Abstract

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.
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This article is cited by 3 publications.
- 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
- 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
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https://doi.org/10.1002/chem.202401955
- 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
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, 8023. https://doi.org/10.3390/ijms25158023
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