Chemical disarming of drug resistance in Mycobacterium tuberculosis

项目摘要/摘要 抗生素耐药性感染是一个危险的世界性健康问题。这些病原体中最主要的是 结核分枝杆菌(Mtb)，估计每年导致150万人死亡。新技术的出现 耐药结核分枝杆菌菌株，占以前治疗的结核病病例的20%，已经 加剧了这一本已令人震惊的流行病。目前的结核病治疗方法的不足之处需要发现 具有独特作用机制的治疗结核分枝杆菌感染的新药物。为此，我们发现 并开发了一种新的化合物家族(称为分枝杆菌耐受抑制物，MTI)，它可以有效地 使结核分枝杆菌对感染期间遇到的压力以及一线抗生素异烟肼(INH)敏感。在……里面 此外，我们还表明，MTI和异丙肾上腺素联合应用阻止了异丙肾上腺素抵抗的选择并恢复异丙肾上腺素 抗异烟肼结核分枝杆菌分离株的活性。据我们所知，MTI是第一份关于 阻断异烟肼耐药性并使抗异烟肼细菌对异烟肼重新敏感的化合物。INH包含在 预防治疗潜伏性结核病和治疗活动性结核病的标准护理(SOC)方案。 不幸的是，耐异烟肼结核病病例的增加正在威胁这种抗生素的相关性，这种抗生素 会在我们的治疗选择上产生很大的差距。小儿麻痹症是抗击结核病的创新战略 抗药性。在初步的机制工作中，我们展示了MTI诱导表达谱和改变 在生理上表明呼吸失调的。因此，我们假设MTI调制了 结核分枝杆菌中的呼吸作用，导致对与呼吸有关的压力的敏化，异烟肼活性的增强， 以及使异烟肼耐药突变株对异烟肼重新敏感，这都将提高抗生素治疗的疗效和 感染期间的免疫反应。我们已经证明了MTI具有药代动力学(PK)特性 适合口服给药，进一步支持了它们转化为人类治疗的承诺。我们的短期计划 目标是展示MTI的临床前概念验证以对抗结核分枝杆菌感染，优化 目前领先的MTIs转化为治疗性药物，并揭示了对药物耐受途径和 抵抗。我们的长期目标是开发一种新的口服抗生素，以改善目前的 用于药物敏感和耐药结核病患者的SOC方案。利用我们在化学方面的综合专业知识 和MTB生物学，我们将通过解决以下独立目标来实现我们的目标：1)优化 通过结构-活性关系(SAR)和结构-性质关系(SPR)研究。2) 剖析MTI影响异烟肼和应激的确切作用模式和详细机制 敏感度。3)检测结核分枝杆菌感染过程中的MTI活性。这些目标的成功实现将 结果是制定了一种创新的治疗战略，以对抗耐药和耐药性。

PROJECT SUMMARY/ABSTRACT Antibiotic resistant infections are a dangerous, worldwide health problem. Chief among these pathogens is Mycobacterium tuberculosis (Mtb), which causes an estimated 1.5 million deaths a year. The emergence of drug-resistant Mtb strains, which constitute 20% of previously treated tuberculosis (TB) cases, has exacerbated this already alarming epidemic. The inadequacies of present TB therapies demand the discovery of new agents with unique mechanisms of action to treat Mtb infection. Towards this end, we have discovered and developed a new family of compounds (termed Mycobacterial Tolerance Inhibitors, MTIs) that potently sensitize Mtb to stresses encountered during infection as well as to the frontline antibiotic isoniazid (INH). In addition, we show that combining MTIs with INH blocks the selection for INH-resistance and restores INH activity in otherwise INH-resistant Mtb isolates. To the best of our knowledge, MTIs are the first report of compounds that block INH resistance and re-sensitize INH-resistant bacteria to INH. INH is included in the standard of care (SOC) regimens for both prophylactic treatment of latent TB as well as treatment of active TB. Unfortunately, the increase in INH-resistant cases of TB is threatening the relevance of this antibiotic, which would generate a large gap in our treatment options. MTIs represent an innovative strategy for combating TB drug resistance. In preliminary mechanistic work, we show that MTIs induce expression profiles and changes in physiology that are indicative of dysregulation of respiration. Therefore, we hypothesize that MTIs modulate respiration in Mtb, leading to sensitization to stresses associated with respiration, potentiation of INH activity, and re-sensitization of INH-resistant mutants to INH, which will all improve the efficacy of antibiotic therapy and immune responses during infection. We have demonstrated that MTIs have pharmacokinetic (PK) properties suitable for oral dosing, further supporting their promise for translation to treatments in humans. Our short-term objectives are to demonstrate preclinical proof-of-concept for MTIs to combat Mtb infection, optimize the current lead MTIs for translation to a therapeutic, and reveal new insights into pathways of drug tolerance and resistance. Our long-term objective is to develop a new orally available antibiotic that improves the current SOC regimens for patients with drug-sensitive and resistant TB. Using our combined expertise in chemistry and Mtb biology, we will achieve our objectives by addressing the following independent aims: 1) Optimize MTIs through structure-activity relationships (SAR) and structure-property relationships (SPR) studies. 2) Dissect the exact mode of action and the detailed mechanisms by which MTIs impact INH and stress sensitivity. 3) Determine the activity of MTIs during Mtb infection. Successful completion of these aims will result in the development of an innovative therapeutic strategy to combat drug tolerance and drug resistance.