结核分枝杆菌中sugI突变介导环丝氨酸耐药的分子机制

耐多药结核病（multidrug-resistant tuberculosis, MDR-TB）治疗困难，且有效药物十分有限。环丝氨酸作为抗结核治疗的核心药物，常组成MDR-TB患者的初始治疗方案。因此一旦环丝氨酸发生耐药，MDR-TB治疗失败风险显著上升。目前所发现与环丝氨酸耐药相关的机制主要包括alr、ddl、cycA、ald等非同义突变。但在临床仍存在部分表型耐药菌株未出现以上四种基因突变，提示有其他耐药机制的存在。为了探究这一问题，我们对这部分耐药菌株进行了菌株全基因组测序，我们筛查到sugI基因发生缺失突变，进一步我们发现sugI基因突变后细菌Alr表达活性的上调。由此我们进一步验证sugI缺失突变后能通过抑制糖外排，增加Alr所需辅因子PLP的含量，从而部分解除环丝氨酸对Alr的抑制作用。同时还将探讨是否存在sugI直接介导环丝氨酸进入结核分枝杆菌内的可能。

Multidrug-resistant tuberculosis (MDR-TB) is difficult to treat, and effective drugs are very limited. As the core drug of anti-tuberculosis treatment, cycloserine often constitutes the initial treatment plan for patients with MDR-TB. Therefore, once resistance to cycloserine develops, the risk of MDR-TB treatment failure increases significantly. At present, the mechanisms related to cycloserine resistance mainly include non-synonymous mutations such as arr, ddl, cycA, and ald. However, there are still some phenotypic drug-resistant strains in the clinic without the above four gene mutations, suggesting that there are other drug resistance mechanisms. In order to explore this problem, we conducted whole-genome sequencing of this part of the drug-resistant strains. We screened for deletion mutations in the sugI gene. Further, we found that the expression activity of bacterial Alr was increased after the sugI gene mutation. Based on this, we further verified that sugI deletion mutation can increase the content of cofactor PLP required by Alr by inhibiting sugar efflux, thereby partially releasing the inhibitory effect of cycloserine on Alr. At the same time, it will also explore whether there is the possibility that sugI directly mediates cycloserine into Mycobacterium tuberculosis.