Drug Targets for Tuberculosis

尽管有抗生素可用，但结核病仍然是全球范围内的主要死亡原因。目前的药物虽然有效且价格低廉，但由于成功治疗所需的疗程非常长，因此很难管理。目前的抗生素需要大量的基础设施来提供和监督治疗，这在世界上许多地方都是一项困难的投资。作用更快的抗生素可能会导致更有效的疾病治愈和控制。 我们之前已经定义了结核分枝杆菌在体外最佳生长所需的一组细菌基因。在这里，我们建议创造有条件地表达基因的菌株，这些基因编码预测的分泌和细胞壁蛋白。这将使我们能够探索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的模式。此外，我们将使用相同的菌株来识别基因，这些基因在灭活时，在感染的小鼠模型中会被迅速清除。最后，我们将使用已经使我们能够识别意想不到的协同药物组合的基因筛查来研究广泛的潜在抗结核化合物。总而言之，这些结果应该允许更合理地选择结核病治疗的目标。

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.