School of Chemistry and Molecular Biosciences, and the Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia.
Mar Drugs. 2024 Jun 28;22(7):298. doi: 10.3390/md22070298.
Tuberculosis remains a significant global health pandemic. There is an urgent need for new anti-tubercular agents to combat the rising incidence of drug resistance and to offer effective and additive therapeutic options. High-throughput screening of a subset of the NatureBank marine fraction library ( = 2000) identified a sample derived from an Australian marine sponge belonging to the order Haplosclerida that displayed promising anti-mycobacterial activity. Bioassay-guided fractionation of the organic extract from this Haplosclerida sponge led to the purification of previously identified antimicrobial pyrrole alkaloids, axinellamines A () and B (). The axinellamine compounds were found to have a 90% minimum inhibitory concentration (MIC) of 18 µM and 15 µM, respectively. The removal of protein and complex carbon sources reduced the MIC of and to 0.6 and 0.8 µM, respectively. The axinellamines were not toxic to mammalian cells at 25 µM and significantly reduced the intracellular bacterial load by >5-fold. These data demonstrate that axinellamines A and B are effective anti-tubercular agents and promising targets for future medicinal chemistry efforts.
结核病仍然是一个重大的全球健康大流行病。急需新的抗结核药物来对抗耐药性的上升，并提供有效和附加的治疗选择。对 NatureBank 海洋部分文库（=2000 个）的亚库进行高通量筛选，鉴定出一种源自澳大利亚海绵的样本，该海绵属于 Haplosclerida 目，显示出有希望的抗分枝杆菌活性。从这种 Haplosclerida 海绵的有机提取物中进行生物测定指导的分级分离，导致了先前鉴定的抗菌吡咯生物碱，轴甲素 A()和 B()的纯化。发现轴甲素化合物的最小抑菌浓度 (MIC) 为 90%，分别为 18 µM 和 15 µM。去除蛋白质和复杂碳源将和的 MIC 降低至分别为 0.6 和 0.8 µM。轴甲素在 25 µM 时对哺乳动物细胞没有毒性，并使细胞内细菌负荷减少 5 倍以上。这些数据表明，轴甲素 A 和 B 是有效的抗结核药物，也是未来药物化学研究的有前途的靶点。
