Yang Dong, Taylor Zachary E, Handy Scott, Li Shaoji, Liu Jiawang, Stabenow Jennifer, Zalduondo Lillian, Jonsson Colleen B, Altman Elliot, Kong Ying
Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States.
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN, United States.
Front Microbiol. 2020 May 20;11:1004. doi: 10.3389/fmicb.2020.01004. eCollection 2020.
The emergence of multidrug-resistant () strains has made tuberculosis (TB) control more difficult. Aurone derivatives have demonstrated promising anti-bacterial activities, but their effects against have not been thoroughly determined. In this study, we aimed to develop anti-TB compounds from aurone analogs. We used a fluorescent protein tdTomato labeled CDC1551 strain to screen 146 synthesized aurone derivatives for effective anti-TB compounds. The 9504, 9505, 9501, 9510, AA2A, and AA8 aurones inhibited the growth of with minimal inhibitory concentrations of 6.25, 12.5, 25, 25, 25, and 50 μM, respectively. We also examined cytotoxicities of the six leads against the human liver cell line HepG2, the primate kidney cell line Vero and human monocyte THP-1 derived macrophages. Three of the aurone leads (9504, 9501, and 9510) showed low cytotoxic effects on all three cell lines and high inhibitory efficacy (selectivity index > 10). Aurone 9504, 9501, AA2A, or AA8 significantly reduced the load in the lungs of infected mice after a 12-days treatment. We determined that the aurone leads inhibit chorismate synthase, an essential enzyme for aromatic acid synthesis. Our studies demonstrate the promise of synthetic aurones as novel anti-TB therapeutics.
多重耐药结核（MDR-TB）菌株的出现使结核病控制变得更加困难。奥洛酮衍生物已显示出有前景的抗菌活性，但其对结核分枝杆菌的作用尚未得到充分确定。在本研究中，我们旨在从奥洛酮类似物开发抗结核化合物。我们使用荧光蛋白tdTomato标记的结核分枝杆菌CDC1551菌株筛选146种合成的奥洛酮衍生物，以寻找有效的抗结核化合物。9504、9505、9501、9510、AA2A和AA8奥洛酮抑制结核分枝杆菌的生长，其最小抑菌浓度分别为6.25、12.5、25、25、25和50μM。我们还检测了这六种先导化合物对人肝癌细胞系HepG2、灵长类肾细胞系Vero和人单核细胞THP-1衍生巨噬细胞的细胞毒性。三种奥洛酮先导化合物（9504、9501和9510）对所有三种细胞系均显示出低细胞毒性和高结核分枝杆菌抑制效力（选择性指数>10）。经12天治疗后，奥洛酮9504、9501、AA2A或AA8显著降低了感染小鼠肺部的结核分枝杆菌载量。我们确定奥洛酮先导化合物抑制分支酸合酶，这是芳香酸合成的一种必需酶。我们的研究证明了合成奥洛酮作为新型抗结核治疗药物的前景。
