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%受到感染。多重耐药微生物广泛存在，广泛耐药微生物正在出现。需要新的方法来对抗这些毒性和耐药生物体（MDR/XDR TB）。所提出的实验旨在表征由M. TB使用胆固醇作为起始材料。假设M.结核病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代表了抗MDR-TB药物开发的新靶标。本工作的目的是确定候选的免疫调节代谢产物产生的M。结核病对胆固醇和巨噬细胞的作用，以推动对负责其形成的基因和相应酶的鉴定。 公共卫生相关性：拟议的研究符合NIAID的目标研究需求，该研究旨在开发针对MDR/XDR TB的新化疗药物。这些实验将为发现调节宿主对结核病免疫反应的代谢物结构提供基础，并指导有效对抗所有形式结核病（包括耐多药/广泛耐多药结核病）的新抗生素的开发。

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.