Wei Wenping, Qiao Junjie, Jiang Xiaofang, Cai Luxia, Hu Xiaomin, He Jin, Chen Min, Yang Min, Cui Tao
College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Front Microbiol. 2022 Apr 19;13:818881. doi: 10.3389/fmicb.2022.818881. eCollection 2022.
Antimicrobial resistance (AMR) represents one of the main challenges in Tuberculosis (TB) treatment. Investigating the genes involved in AMR and the underlying mechanisms holds promise for developing alternative treatment strategies. The results indicate that dehydroquinate synthase (DHQS) regulates the susceptibility of BCG to first-line anti-TB drug streptomycin. Perturbation of the expression of encoding DHQS affects the susceptibility of BCG to streptomycin. Purified DHQS impairs antibacterial activity of streptomycin, but did not hydrolyze or modify streptomycin. DHQS directly binds to streptomycin while retaining its own catalytic activity. Computationally modeled structure analysis of DHQS-streptomycin complex reveals that DHQS binds to streptomycin without disturbing native substrate binding. In addition, streptomycin treatment significantly induces the expression of DHQS, thus resulting in DHQS-mediated susceptibility. Our findings uncover the additional function of DHQS in AMR and provide an insight into a non-canonical resistance mechanism by which protein hijacks antibiotic to reduce the interaction between antibiotic and its target with normal protein function retained.
抗菌耐药性（AMR）是结核病（TB）治疗中的主要挑战之一。研究与AMR相关的基因及其潜在机制有望开发出替代治疗策略。结果表明，脱氢奎尼酸合酶（DHQS）调节卡介苗对一线抗结核药物链霉素的敏感性。编码DHQS的基因表达受到干扰会影响卡介苗对链霉素的敏感性。纯化的DHQS会削弱链霉素的抗菌活性，但不会水解或修饰链霉素。DHQS直接与链霉素结合，同时保留其自身的催化活性。对DHQS-链霉素复合物的计算建模结构分析表明，DHQS与链霉素结合而不会干扰天然底物的结合。此外，链霉素处理会显著诱导DHQS的表达，从而导致DHQS介导的敏感性。我们的研究结果揭示了DHQS在AMR中的额外功能，并深入了解了一种非经典的耐药机制，即蛋白质劫持抗生素以减少抗生素与其靶点之间的相互作用，同时保留正常的蛋白质功能。
