Chemical disarming of drug resistance in Mycobacterium tuberculosis

项目总结/摘要 抗生素耐药性感染是一个危险的全球性健康问题。这些病原体中最主要的是 结核分枝杆菌（Mtb），估计每年造成150万人死亡。的出现 耐药结核分枝杆菌菌株占先前治疗的结核病（TB）病例的20%， 加剧了这一本已令人担忧的流行病。目前结核病治疗的不足之处需要发现 具有独特作用机制的新药物来治疗Mtb感染。为此，我们发现 并开发了一种新的化合物家族（称为分枝杆菌耐受性抑制剂，MTIs）， 使结核分枝杆菌对感染期间遇到的压力以及对一线抗生素异烟肼（INH）敏感。在 此外，我们发现MTIs与INH的结合阻断了INH抗性的选择，并恢复了INH 在其他INH抗性Mtb分离株中的活性。据我们所知，多边贸易体制是第一个报告， 阻断INH抗性并使INH抗性细菌对INH重新敏感的化合物。INH包括在 用于预防性治疗潜伏性TB以及治疗活动性TB的标准护理（SOC）方案。 不幸的是，结核病中INH耐药病例的增加正在威胁这种抗生素的相关性， 会给我们的治疗方案带来很大的缺口MTIs代表了一种抗击结核病的创新战略 耐药性在初步的机制研究中，我们发现MTIs诱导表达谱和变化， 在生理学上是呼吸失调的标志。因此，我们假设MTIs调节 Mtb中的呼吸，导致对与呼吸相关的应激的敏感性，INH活性的增强， 以及INH抗性突变体对INH的再致敏，这都将提高抗生素治疗的功效， 感染时的免疫反应。我们已经证明MTIs具有药代动力学（PK）特性， 适合口服给药，进一步支持其转化为人类治疗的前景。我们的短期 目的是证明MTIs对抗Mtb感染的临床前概念验证，优化 目前的领导MTIs翻译为治疗，并揭示了新的见解，药物耐受性的途径， 阻力我们的长期目标是开发一种新的口服抗生素， 药物敏感和耐药TB患者的SOC方案。利用我们在化学方面的综合专业知识 和结核分枝杆菌生物学，我们将通过解决以下独立目标来实现我们的目标：1）优化 通过构效关系（SAR）和结构-性质关系（SPR）研究MTIs。（二） 剖析MTIs影响INH和应激的确切作用模式和详细机制 灵敏度3)确定Mtb感染期间MTIs的活性。成功实现这些目标将 导致开发了一种创新的治疗策略，以对抗药物耐受性和耐药性。

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.