Investigation of the mechanisms and effects of riboregulation of iron homeostasis in M. tuberculosis

摘要 结核病(TB)是世界范围内的一个重大公共卫生问题。尽管死亡人数 由于诊断和早期治疗的改进，结核病近年来有所减少， 抗生素耐药性的持续增加和新药的短缺 结核分枝杆菌有可能破坏结核病控制努力。我们的研究重点是 利用结核分枝杆菌(Mtb)对铁失调的敏感性来产生新的治疗方法 防止结核分枝杆菌毒力和加强抗生素作用的策略。 铁是结核分枝杆菌建立生产性感染所必需的一种基本微量营养素。 然而，过量的铁可能是非常有毒的，因为这种金属倾向于催化 产生活性氧物种，这会损害所有大分子。就像所有的铁一样- 依赖细胞，结核分枝杆菌必须平衡细胞内的铁水平，因为它遇到了不同的铁 主机中的环境。来自动物研究的证据表明，维持铁的能力 动态平衡对结核分枝杆菌的增殖和致病至关重要。反过来，我们之前的研究 确定结核分枝杆菌依赖于全球转录调控因子IDER来控制铁 动态平衡。 我们的初步研究确定了一种天然的反义转录本(IDER-AS)能够诱导 在结核分枝杆菌中反式表达时铁的失调。尽管这种RNA改变了 受ider控制的基因，它似乎并不通过改变ider水平和它的作用模式而起作用。 是不理解的。我们假设iDER-AS调节iDER活动。我们的目标是 建议调查iDER-AS的行动模式，并评估iDER-AS之间的协同作用 还有抗生素。我们预计，破译这种RNA如何影响铁的调节将指导 针对结核分枝杆菌铁稳态的努力。

Summary Tuberculosis (TB) is a significant public health problem worldwide. Although the number of deaths due to TB has decreased in recent years thanks to improved diagnostics and early treatment, the sustained increase in antibiotic resistance and the shortage of new effective drugs against Mycobacterium tuberculosis threatens to undermine TB control efforts. Our studies focus on exploiting M. tuberculosis (Mtb) sensitivity to iron dysregulation to generate new therapeutic strategies that prevent Mtb virulence and potentiate antibiotic action. Iron is an essential micronutrient required by M. tuberculosis to establish a productive infection. However, excess iron can be very toxic due to the propensity of this metal to catalyze the production of reactive oxygen species, which can damage all macromolecules. Like all iron- dependent cells, Mtb must balance intracellular iron levels as it encounters diverse iron environments in the host. Evidence from animal studies indicates that the ability to maintain iron homeostasis is essential for Mtb to proliferate and cause disease. In turn, our previous studies established that Mtb depends on the global transcriptional regulator, IdeR, to control iron homeostasis. Our preliminary studies characterized a natural antisense transcript (IdeR-AS) capable of inducing iron dysregulation when expressed in trans in Mtb. Although this RNA alters the expression of genes controlled by IdeR, it does not seem to act by altering IdeR levels, and its mode of action is not understood. We hypothesize that IdeR-AS modulates IdeR activity. Our goals for this proposal are to investigate IdeR-AS mode of action and evaluate the synergy between IdeR-AS and antibiotics. We expect that deciphering how this RNA influences iron regulation would guide efforts to target iron homeostasis in Mtb.