抗细菌
金丝桃苷
结核分枝杆菌
化学
微生物学
药理学
肺结核
贯叶连翘
生物
医学
病理
作者
Philipp Peslalz,Mark Grieshober,Frank Kraus,Anton Bleisch,Flavia Izzo,Dajana Lichtenstein,Helen Hammer,Andreas Vorbach,Kyoko Momoi,Ulrich M. Zanger,Heike Brötz‐Oesterhelt,Albert Braeuning,Bernd Plietker,Steffen Stenger
标识
DOI:10.1021/acs.jmedchem.3c01172
摘要
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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