Nitschke Jahn, Huber Robin, Vossio Stefania, Moreau Dimitri, Marcourt Laurence, Gindro Katia, Queiroz Emerson F, Soldati Thierry, Hanna Nabil
Department of Biochemistry, Faculty of Science, University of Geneva, Geneva, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland.
Front Microbiol. 2024 Sep 17;15:1439814. doi: 10.3389/fmicb.2024.1439814. eCollection 2024.
(Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases.
This study evaluated the suitability of a high-throughput infection system composed of the host amoeba (Dd) and (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes.
The study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of -δ-viniferins and in particular of two compounds and with an IC of 18.1 μM, 9 μM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense.
The study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.
结核分枝杆菌（Mtb）是结核病的病原体，在全球范围内仍然对人类健康构成严重威胁，寻求新型抗结核药物是一个持久且艰巨的过程。天然产物在推进传染病药物治疗方面发挥了重要作用。
本研究评估了由宿主变形虫（Dd）和结核分枝杆菌的近亲（Mm）组成的高通量感染系统用于鉴定抗感染化合物的适用性。在表型分析中，通过发光和荧光读数对Dd的生长和细胞内Mm进行定量。该系统首先用一组治疗性抗结核分枝杆菌抗生素进行基准测试，然后用于筛选生物转化的芪类化合物文库。
该研究证实了利福平、贝达喹啉等已确立的抗生素的疗效，其活性低于规定的抗分枝杆菌药敏阈值，同时也证实了吡嗪酰胺对Mm无活性。筛选揭示了-δ-葡萄素具有有前景的抗感染活性，特别是两种化合物，其半数抑制浓度（IC）分别为18.1μM、9μM。两种化合物在肉汤中对Mm均无活性。随后通过卤化和构效关系研究进行的探索导致了具有改善的选择性和效力的衍生物的鉴定。抗感染化合物的作用方式可能涉及抑制分枝杆菌毒力因子或增强宿主防御。
该研究突出了生物转化和受天然产物启发的衍生化方法在药物发现中的潜力，并强调了Dd-Mm感染系统在鉴定新型抗感染化合物方面的实用性。
