Drug Targets for Tuberculosis

尽管有抗生素，结核病仍然是全世界死亡的主要原因。目前的药物虽然有效且便宜，但由于成功治疗所需的疗程非常长，因此很难施用。目前的抗生素需要大量的基础设施来提供和监督治疗，这在世界许多地方都是困难的投资。作用更迅速的抗生素可以更有效地治愈和控制疾病。 我们之前已经定义了结核分枝杆菌最佳体外生长所需的一组细菌基因。在这里，我们建议创建有条件表达编码预测的分泌蛋白和细胞壁蛋白的基因的菌株。这将使我们能够探究它们在各种生长条件下的重要性，包括细菌快速生长的条件和各种非复制持久性模型。此外，我们将使用相同的菌株来鉴定基因，这些基因在失活后会在小鼠感染模型中迅速被清除。最后，我们将使用基因筛选，该筛选已经使我们能够识别出意想不到的协同药物组合，以研究广泛的潜在抗结核化合物。总而言之，这些结果应该有助于更合理地选择结核病治疗靶点。

Despite the availability of antibiotics, tuberculosis remains a major cause of death worldwide. Current drugs, while effective and inexpensive, are quite difficult to administer because of the very extended courses of treatment required for successful therapy. Current antibiotics require a substantial infrastructure to deliver and supervise therapy, an investment that is difficult in much of the world. Antibiotics that acted more rapidly could lead to much more effective cure and control of disease. We have previously defined the set of bacterial genes that are required for optimal in vitro growth of Mycobacterium tuberculosis. Here we propose to create strains that conditionally express genes that encode predicted secreted and cell wall proteins. This will enable us to probe their importance under various growth conditions, including those in which bacteria are growing rapidly and various models of nonreplicating persistence. In addition, we will use the same strains to identify genes which, when inactivated, are cleared rapidly in a mouse model of infection. Finally, we will use a genetic screen that has already enabled us to identify unexpected synergistic drug combinations to study a broad range of potential antituberculous compounds. Altogether, these results should allow more rational selection of targets for treatment of tuberculosis.