Choi Seoung-ryoung, Larson Marilynn A, Hinrichs Steven H, Narayanasamy Prabagaran
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900, United States.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900, United States.
Bioorg Med Chem Lett. 2016 Apr 15;26(8):1997-9. doi: 10.1016/j.bmcl.2016.02.087. Epub 2016 Mar 2.
DNA-dependent RNA primase is essential for de novo primer synthesis during DNA replication in all living organisms. Bacterial DnaG primase is an attractive target for inhibition because it is essential, low in copy number and structurally distinct from eukaryotic and archaeal primases. DnaG primase is sensitive to known inhibitors including suramin and doxorubicin. Recently, tilorone was discovered by high throughput screening to be an inhibitor of Bacillus anthracis primase DnaG but it failed to reduce the growth of B. anthracis in vitro. In this study we determined that tilorone also inhibited DnaG primase from Staphylococcus aureus. C2-Symmetric fluorenone-based compounds, similar to tilorone chemical structure were synthesized and tested to identify potential lead compounds that inhibit bacterial growth in B. anthracis, MRSA and Burkholderia thailandensis. These compounds were evaluated by determining the minimum inhibitory concentration (MIC) against several different bacterial species which demonstrated 17.5 and 16 μg/ml MIC profiles. Importantly, some of the fluorenone-based compounds with a long carbon chain showed a relatively low MIC against B. anthracis, S. aureus, MRSA, Francisella tularensis, and B. thailandensis, suggesting it may be a promising lead compound.
DNA 依赖性 RNA 引物酶对于所有生物体 DNA 复制过程中的从头合成引物至关重要。细菌 DnaG 引物酶是一个有吸引力的抑制靶点，因为它是必需的，拷贝数低，并且在结构上与真核生物和古细菌引物酶不同。DnaG 引物酶对包括苏拉明和阿霉素在内的已知抑制剂敏感。最近，通过高通量筛选发现替洛龙是炭疽芽孢杆菌引物酶 DnaG 的抑制剂，但它未能在体外降低炭疽芽孢杆菌的生长。在本研究中，我们确定替洛龙也能抑制金黄色葡萄球菌的 DnaG 引物酶。合成了与替洛龙化学结构相似的 C2 对称芴酮类化合物，并进行测试以鉴定抑制炭疽芽孢杆菌、耐甲氧西林金黄色葡萄球菌和泰国伯克霍尔德菌生长的潜在先导化合物。通过测定对几种不同细菌物种的最低抑菌浓度（MIC）来评估这些化合物，结果显示 MIC 为 17.5 和 16 μg/ml。重要的是，一些具有长碳链的芴酮类化合物对炭疽芽孢杆菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、土拉弗朗西斯菌和泰国伯克霍尔德菌显示出相对较低的 MIC，表明它可能是一种有前途的先导化合物。
