Carbon monoxide resistance in Mycobacterium tuberculosis pathogenesis

描述（由申请人提供）：结核分枝杆菌仍然是最具破坏性的人类传染病之一，每年造成200万人死亡，并潜伏感染世界三分之一的人口。作为一种适应长期生存的胞内病原菌，M.结核病已经进化出抵抗宿主抗微生物途径杀死的机制。针对这些耐药机制最近已成为治疗M的一种强有力的新方法。通过增强宿主消灭细菌的能力来预防结核病感染。然而，分枝杆菌耐药基因的完整库尚不清楚，扩大这一知识基础为新药的开发提供了额外的途径。我们展示了M。结核病诱导一种酶，血红素加氧酶，产生一氧化碳（CO）气体，并且M.结核杆菌既适应又抵抗CO的杀伤。结核分枝杆菌进化出了抗CO的基因，我们的初步数据表明，M.结核病编码一种这样的基因，当突变时导致毒力减弱。我们将应用代谢组学、转录组学、蛋白质组学和生物化学方法来确定新发现的抗CO蛋白的功能。因此，在拟议的研究中，我们将（1）确定CO抗性的分子机制，（2）确定CO抗性基因的相互作用伴侣及其在CO抗性中的作用，（3）表征CO抗性基因及其相互作用伴侣突变体的致病作用。本文的工作将扩展现有的关于M.结核病的耐药性机制，并揭示了一种新的微生物生存策略。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis remains one of the most devastating human infectious diseases, causing two million deaths annually and latently infecting a third of the world's population. As an intracellular pathogen adapted to long-term survival, M. tuberculosis has evolved mechanisms to resist killing by host antimicrobial pathways. Targeting those resistance mechanisms has recently emerged as a powerful new approach to treating M. tuberculosis infection by enhancing the host's ability to eradicate the bacteria. However, the full repertoire of mycobacterial resistance genes is not known, and expanding this knowledge base provides additional avenues for the development of new drugs. We demonstrated the M. tuberculosis induces an enzyme, heme oxygenase, that produces carbon monoxide (CO) gas, and that M. tuberculosis both adapts to and resists killing by CO. We hypothesized that M. tuberculosis evolved genes for CO resistance, and our preliminary data indicate that M. tuberculosis encodes one such gene that when mutated results in attenuated virulence. We will apply metabolomic, transcriptomic, proteomic, and biochemical approaches to determine the function of the newly discovered CO resistance protein. Thus, in the proposed research we will (1) identify the molecular mechanism of CO resistance, (2) determine the interacting partners of the CO resistance gene and their role in CO resistance and (3) characterize the pathogenic effects of mutants in the CO resistance gene and its interacting partners. The proposed work will extend the current knowledge on M. tuberculosis's antimicrobial resistance mechanisms and reveal a novel microbial survival strategy.