Biotin synthesis and biotin ligation in Mtb

描述(由申请人提供)：结核病(TB)仍然是人类因单一传染病而死亡的第二大原因。对多药耐药(MDR)或极端耐药(XDR)的结核分枝杆菌菌株继续出现和传播。需要新药来限制结核病对全球公共健康的影响。我们证明了生物素代谢对结核分枝杆菌在感染期间的生长和持久性是必不可少的，生物素饥饿可以导致细菌细胞死亡，并确定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的脆弱性，(Ii)确定结核分枝杆菌生物素饥饿诱导细胞死亡的触发因素，(Iii)利用基于结构的药物设计来进一步开发可抑制结核分枝杆菌生物素代谢的现有先导化合物，以及(Iv)研究这些抑制物的作用机制。

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.