Steroid Hormone Biosynthesis by M.tb

描述（由申请人提供）：世界卫生组织估计，每年有200万人死于结核病，世界人口的30%被感染。多重耐药菌广泛存在，广泛耐药菌正在出现。需要新的方法来对抗这些毒性和耐药生物（耐多药/广泛耐药结核病）。提出的实验旨在表征结核分枝杆菌产生的代谢产物，以胆固醇为起始材料。假设是结核分枝杆菌将胆固醇转化为调节宿主免疫系统的激素。催化激素合成的相应酶活性是抗耐多药结核病药物开发的新目标。这项工作的目的是鉴定结核分枝杆菌在胆固醇和巨噬细胞生长过程中产生的候选免疫调节代谢物，以推动鉴定负责其形成的基因和相应的酶。

DESCRIPTION (provided by applicant): The World Health Organization estimates that 2 million people die every year from tuberculosis and that 30% of the world's population is infected. Multi-drug resistant organisms are widespread and extensively drug resistant organisms are emerging. New approaches are required to combat these virulent and drug resistant organisms (MDR/XDR TB). The proposed experiments are aimed at characterizing metabolites produced by M. tb using cholesterol as a starting material. The hypothesis is that M. tb transforms cholesterol to hormones that regulate the host immune system. The corresponding enzymatic activities that catalyze hormone synthesis represent new targets for anti-MDR-TB pharmaceutical development. The aim of this work is to identify candidate immunomodulatory metabolites produced during growth of M. tb on cholesterol and in macrophages in order to drive the identification of the genes and corresponding enzymes responsible for their formation. PUBLIC HEALTH RELEVANCE: The proposed research fits within the targeted research needs of NIAID that seeks the development of new chemotherapeutic agents against MDR/XDR TB. These experiments will provide a basis for discovering the structure of metabolites that regulate the host immune response to TB and guide development of new antibiotics that would be effective against all forms of TB including MDR/XDR TB.