| Autor: |
Peslalz P; Chair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,Germany., Grieshober M; Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Albert-Einstein-Allee 11, Ulm D-89081, Germany., Kraus F; Institut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, Germany., Bleisch A; Chair of Organic Chemistry, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Bergstr. 66, Dresden01069 ,Germany., Izzo F; Institut für Organische Chemie, Universität Stuttgart,Pfaffenwaldring 55, Stuttgart 70569, Germany., Lichtenstein D; Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, Germany., Hammer H; SIGNATOPE GmbH, Markwiesenstr. 55, Reutlingen 72770, Germany., Vorbach A; Interfaculty Institute of Microbiology and Infection Medicine, Tübingen 72076, Germany., Momoi K; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Auerbachstr. 112, University of Tübingen, 70376 Stuttgart, Tübingen 72076, Germany., Zanger UM; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Auerbachstr. 112, University of Tübingen, 70376 Stuttgart, Tübingen 72076, Germany., Brötz-Oesterhelt H; Interfaculty Institute of Microbiology and Infection Medicine, Tübingen 72076, Germany.; German Center for Infection Research, Partner Site Tübingen, Tübingen 72076, Germany., Braeuning A; Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, Germany., Plietker B; 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., Stenger S; Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Albert-Einstein-Allee 11, Ulm D-89081, Germany. |
| Abstrakt: |
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. |
