Dipartimento di Genetica e Microbiologia, Università degli Studi di Pavia, Pavia, Italy.
Curr Med Chem. 2010;17(27):3099-108. doi: 10.2174/092986710791959693.
Tuberculosis is still a leading cause of death in developing countries and a resurgent disease in developed countries. The selection and soaring spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Currently, there is an urgent need of new drugs for tuberculosis treatment, with novel mechanisms of action and, moreover, the necessity to identify new drug targets. Several enzymes involved in various metabolic processes have been described as potential targets for the development of new drugs. Recently, two different classes of most promising drugs, the benzothiazinones (BTZ) and the dinitrobenzamide derivatives (DNB), have been found to be highly active against M. tuberculosis, including XDR-TB strains. Interestingly, both drugs have the same target: the heteromeric decaprenylphosphoryl-β-D-ribose 2'-epimerase encoded by dprE1 (Rv3790) and dprE2 (Rv3791) genes, respectively. DprE1 and DprE2 are involved in the biosynthesis of D-arabinose and, in particular, they are essential to perform the transformation of decaprenylphosphoryl-D-ribose to decaprenylphosphoryl-D-arabinose, which is a substrate for arabinosyltransferases in the synthesis of the cell-envelope arabinogalactan and liporabinomannan polysaccharides of mycobacteria. Arabinogalactan is a fundamental component of the mycobacterial cell wall, which covalently binds the outer layer of mycolic acids to peptidoglycan. The heteromeric decaprenylphosphoryl-β-D-ribose 2'-epimerase thus represents a valid vulnerable antimycobacterial drug target which could result in "magic" for tuberculosis treatment.
结核病仍然是发展中国家的主要死因，也是发达国家重新出现的疾病。结核分枝杆菌多药耐药（MDR-TB）和广泛耐药（XDR-TB）的选择和传播是一个严重的公共卫生问题。目前，迫切需要新的结核病治疗药物，具有新的作用机制，而且有必要确定新的药物靶点。已经描述了几种参与各种代谢过程的酶作为开发新药物的潜在靶点。最近，两种不同类别的最有前途的药物，苯并噻嗪酮（BTZ）和二硝基苯甲酰胺衍生物（DNB），已被发现对结核分枝杆菌，包括 XDR-TB 菌株具有高度活性。有趣的是，这两种药物的靶标相同：分别由 dprE1（Rv3790）和 dprE2（Rv3791）基因编码的异源二聚体脱磷酸-D-核糖 2'-差向异构酶。DprE1 和 DprE2 参与 D-阿拉伯糖的生物合成，特别是它们对于将脱磷酸-D-核糖转化为脱磷酸-D-阿拉伯糖是必不可少的，脱磷酸-D-阿拉伯糖是阿拉伯糖基转移酶合成分枝杆菌细胞壁阿拉伯半乳聚糖和脂阿拉伯甘露聚糖多糖的底物。阿拉伯半乳聚糖是分枝杆菌细胞壁的基本成分，它将外层的类脂酸共价结合到肽聚糖上。异源二聚体脱磷酸-D-核糖 2'-差向异构酶因此代表了一个有效的脆弱的抗分枝杆菌药物靶点，这可能会对结核病治疗产生“神奇”的效果。
