Deciphering the structure activity relationship, mode of action and uptake of isonitrile antibiotics in Gram-negative bacteria

破译革兰氏阴性菌中异腈抗生素的结构活性关系、作用方式和摄取

• 批准号: 505074737
• 负责人: Professor Dr. Stephan A. Sieber
• 金额: --
• 依托单位: Lehrstuhl für Organische Chemie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505074737?language=en
• 关键词: Deciphering; structure; activity; relationship; mode

Infectious diseases caused by multiresistant pathogenic bacteria pose a major threat to public health. Especially Gram-negative bacteria such as Acinetobacter baumannii are of urgent need for novel drug development as almost no treatment options are left. Deciphering new antibiotics against these strains is challenged by the limited scope of currently exploited targets, diverse resistance strategies as well as a largely impermeable cell membrane. Thus, new approaches are needed to decipher novel modes of action (MoA) as well as clever uptake strategies. In the past, natural products have been a great source for potent antibiotics displaying various structural features even facilitating the entry into Gram-negative cells. Many of these compounds, despite potent antibiotic effects, have not been followed up. Given the current drought in the development pipeline their systematic characterization may lead to novel MoAs and corresponding drugs.We recently deciphered the MoA of xanthocillin, an isonitrile antibiotic discovered in 1948, with potent nM activity against A. baumannii. The molecule scavenges free heme in the bacterial cell and thereby dysregulates its biosynthesis leading to death by oxidative stress. We here would like to decipher how xanthocillin binds to heme by structure activity relationship studies. We thus aim to exploit the roles of the vinyl groups, the isonitriles as well as the aromatic ring system by the synthesis of diverse analogs. Crystallization with heme will unravel the binding mode and provide a rational for compound fine tuning. Moreover, we turn our attention to another isonitrile natural product antibiotic, B371, synthesize a chemical probe and investigate its cellular targets with our established chemical proteomic platform. As this molecule is structurally different and does only bear one isonitrile group, we anticipate a heme-independent MoA. Finally, we use tailored photoprobes to unravel the enigmatic uptake mechanisms of isonitriles into Gram-negative cells. Overall, these studies will contribute to a deeper understanding of a so far neglected group of antibiotics and their novel MoA.

由多重耐药病原菌引起的传染病对公众健康构成重大威胁。尤其是革兰氏阴性菌，如鲍曼不动杆菌，由于几乎没有治疗选择，迫切需要新药开发。目前开发的靶点范围有限、耐药策略多样以及细胞膜基本上不渗透，因此破解这些菌株的新抗生素面临着挑战。因此，需要新的方法来破译新的作用模式（MoA）以及巧妙的吸收策略。过去，天然产物一直是强效抗生素的重要来源，这些抗生素具有各种结构特征，甚至有助于进入革兰氏阴性细胞。尽管这些化合物具有有效的抗生素作用，但其中许多化合物尚未得到后续研究。鉴于目前开发渠道的匮乏，对它们的系统表征可能会产生新型 MoA 和相应的药物。我们最近破译了黄青霉素的 MoA，黄青霉素是 1948 年发现的一种异腈抗生素，对鲍曼不动杆菌具有强大的 nM 活性。该分子清除细菌细胞中的游离血红素，从而调节其生物合成，导致氧化应激死亡。我们想通过结构活性关系研究来解读黄霉素如何与血红素结合。因此，我们的目标是通过合成不同的类似物来开发乙烯基、异腈以及芳环系统的作用。血红素结晶将揭示结合模式并为化合物微调提供合理依据。此外，我们将注意力转向另一种异腈天然产物抗生素 B371，合成化学探针并利用我们已建立的化学蛋白质组平台研究其细胞靶点。由于该分子结构不同并且仅带有一个异腈基团，因此我们预计会出现一种不依赖于血红素的 MoA。最后，我们使用定制的光探针来解开异腈进入革兰氏阴性细胞的神秘摄取机制。总的来说，这些研究将有助于更深入地了解迄今为止被忽视的一组抗生素及其新型作用机制。