Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Sci Rep. 2018 Nov 28;8(1):17439. doi: 10.1038/s41598-018-35701-z.
The anti-tuberculosis (TB) agent IMB-T130 was speculated to be a multi-target compound. In this research, we found that IMB-T130 inhibits the catalytic activity of Mycobacterium tuberculosis 3-dehydroquinate synthase (MtDHQS), the enzyme in the second step of the shikimate pathway. IMB-T130 was identified as a selective inhibitor of MtDHQS with an IC value of 0.87 μg/mL. The interaction between the compound and protein was analysed by surface plasmon resonance and circular dichroism. Based on the in silico molecular docking results, the essential amino acids in the binding pocket were then confirmed by site-directed mutagenesis. Overexpression of DHQS reduced the antibacterial activity of IMB-T130 in cells, verifying that DHQS is the target of IMB-T130. IMB-T130 inhibited standard and drug-resistant M. tuberculosis strains by targeting DHQS. Our findings improve our understanding of MtDHQS and make it to be a potential target for new anti-TB drug discovery.
抗结核（TB）药物 IMB-T130 被推测为一种多靶化合物。在这项研究中，我们发现 IMB-T130 抑制分枝杆菌 3-脱氢奎宁酸合酶（MtDHQS）的催化活性，该酶是莽草酸途径的第二步中的酶。IMB-T130 被鉴定为 MtDHQS 的选择性抑制剂，IC 值为 0.87μg/mL。通过表面等离子体共振和圆二色性分析了化合物与蛋白质的相互作用。基于计算机分子对接结果，然后通过定点突变确认了结合口袋中的必需氨基酸。DHQS 的过表达降低了 IMB-T130 在细胞中的抗菌活性，证实 DHQS 是 IMB-T130 的靶标。IMB-T130 通过靶向 DHQS 抑制标准和耐药结核分枝杆菌菌株。我们的发现提高了我们对 MtDHQS 的认识，并使其成为新的抗结核药物发现的潜在靶标。
