1 Department of Biochemistry, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, India.
SLAS Discov. 2017 Dec;22(10):1229-1238. doi: 10.1177/2472555217698428. Epub 2017 Mar 17.
Tuberculosis still remains one of the most fatal infectious diseases. Streptomycin (SM) is the drug of choice, especially for patients with multidrug-resistant tuberculosis or category II patients, because it targets the protein synthesis machinery by interacting with steps of translation. Several mechanisms have been proposed to explain the resistance, but our knowledge is inadequate. Secretome often plays an important role in pathogenesis and is considered an attractive reservoir for the development of novel diagnostic markers and targets. In this study, we analyze the secretory proteins of streptomycin-resistant Mycobacterium tuberculosis isolates by 2-dimensional gel electrophoresis-matrix assisted laser desorption/ionization-time-of-flight mass spectrometry and bioinformatic tools. Fifteen overexpressed proteins were identified in a resistant isolate that belonged to various categories such as virulence/detoxification/adaptation, intermediary metabolism and respiration, and conserved hypotheticals. Among them, Rv1860, Rv1980c, Rv2140c, Rv1636, and Rv1926c were proteins of an undefined role. Molecular docking of these proteins with SM showed that it binds to their conserved domains and suggests that these might neutralize/compensate the effect of the drug. The interactome also suggests that overexpressed proteins along with their interactive partner might be involved in M. tuberculosis virulence and resistance. The cumulative effect of these overexpressed proteins could involve SM resistance, and these might be used as diagnostic markers or potential drug targets.
结核病仍然是最致命的传染病之一。链霉素（SM）是首选药物，特别是对耐多药结核病或 II 类患者，因为它通过与翻译步骤相互作用靶向蛋白质合成机制。已经提出了几种解释耐药性的机制，但我们的知识还不够充分。分泌组在发病机制中经常起着重要作用，被认为是开发新型诊断标志物和靶标的有吸引力的库。在这项研究中，我们通过二维凝胶电泳-基质辅助激光解吸/电离-飞行时间质谱和生物信息学工具分析了耐链霉素分枝杆菌分离株的分泌蛋白。在一个耐药分离株中鉴定出 15 种过表达蛋白，它们属于各种类别，如毒力/解毒/适应、中间代谢和呼吸以及保守的假设。其中，Rv1860、Rv1980c、Rv2140c、Rv1636 和 Rv1926c 是具有未知作用的蛋白质。这些蛋白质与 SM 的分子对接表明，它与它们的保守结构域结合，并表明这些可能中和/补偿药物的作用。互作组还表明，过表达的蛋白质及其相互作用的伴侣可能参与分枝杆菌的毒力和耐药性。这些过表达蛋白的累积效应可能涉及 SM 耐药性，并且这些蛋白可以用作诊断标志物或潜在的药物靶点。
