Biotin synthesis and biotin ligation in Mtb

描述（由申请人提供）：结核病（TB）仍然是单一传染性病原体导致人类死亡的第二大原因。耐多种药物（MDR）或极度耐药（XDR）的结核分枝杆菌菌株继续出现并传播。需要新的药物来限制结核病对全球公共卫生的影响。我们证明了生物素代谢对结核分枝杆菌感染期间的生长和持续至关重要，生物素饥饿可导致细菌细胞死亡，我们发现了结核分枝杆菌生物素蛋白连接酶的抑制剂。在拟议的研究中，我们将(i)测量结核分枝杆菌对参与生物素代谢的不同酶的抑制脆弱性，（ii）确定生物素饥饿诱导的结核分枝杆菌细胞死亡的触发因素，（iii）使用基于结构的药物设计进一步开发抑制结核分枝杆菌生物素代谢的可用先导化合物，以及（iv）研究这些抑制剂的作用机制。

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains the second leading cause of human death from a single infectious agent. Mycobacterium tuberculosis strains that are resistant against multiple drugs (MDR) or are extremely drug resistant (XDR) continue to emerge and spread. New drugs are needed limit the impact of TB on global public health. We demonstrated that biotin metabolism is essential for growth and persistence of M. tuberculosis during infections, that biotin starvation can cause bacterial cell death, and we identified inhibitors of the biotin protein ligase of M. tuberculosis. In the proposed research we will (i) measure vulnerability of M. tuberculosis towards inhibition of different enzymes participating in biotin metabolism, (ii) identify triggers of biotin-starvation-induced cell death in M. tuberculosis, (iii) use structure-based drug design to further develop available lead compounds that inhibit biotin metabolism in M. tuberculosis, and (iv) study the mechanism of action of these inhibitors.