Chemical disarming of drug resistance in Mycobacterium tuberculosis

结核分枝杆菌耐药性的化学解除

• 批准号: 10190796
• 负责人: Fredrik Almqvist
• 金额: $ 66.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-16 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190796
• 关键词: Address; Antibiotic Therapy; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Biological Assay; Biology; Cessation of life; Chemicals; Chemistry; Chemosensitization; Clinic; Clinical; Dangerousness; Data; Development; Dose; Drug Kinetics; Drug Sensitization; Drug Tolerance; Drug resistance; Drug resistance in tuberculosis; Epidemic; Family; Formulation; Future; Health; Human; Immune response; Incidence; Infection; Isoniazid resistance; Lead; Modeling; Modification; Monitor; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; New Agents; Oral; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiology; Plasma; Process; Property; Prophylactic treatment; Regimen; Reporting; Resistance; Respiration; Solubility; Stress; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Uses; Translations; Tuberculosis; Water; Work; active method; analog; antibiotic resistant infections; bacterial resistance; combat; design; drug development; drug discovery; drug-sensitive; fighting; improved; inhibitor/antagonist; innovation; insight; isoniazid; mutant; mycobacterial; novel; novel therapeutic intervention; pathogen; pre-clinical; prevent; scalpel; standard of care; tuberculosis drugs; tuberculosis treatment

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.

项目概要/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)，估计每年导致 150 万人死亡。的出现 耐药 Mtb 菌株占既往治疗的结核病 (TB) 病例的 20%， 加剧了这一本已令人震惊的流​​行病。现有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可治疗结核分枝杆菌感染。为此，我们发现 并开发了一个新的化合物家族（称为分枝杆菌耐受抑制剂，MTIs），可以有效地 使 Mtb 对感染过程中遇到的压力以及一线抗生素异烟肼 (INH) 敏感。在 此外，我们发现将 MTI 与 INH 结合可以阻止对 INH 抗性的选择并恢复 INH 在其他 INH 抗性 Mtb 分离株中的活性。据我们所知，MTIs 是第一份报告 阻断 INH 耐药性并使 INH 耐药细菌对 INH 重新敏感的化合物。 INH 包含在 用于潜伏性结核病预防性治疗和活动性结核病治疗的标准护理 (SOC) 方案。 不幸的是，INH 耐药结核病病例的增加正在威胁这种抗生素的相关性， 将会在我们的治疗选择上产生很大的差距。 MTI 代表了抗击结核病的创新战略 耐药性。在初步机制工作中，我们表明 MTI 诱导表达谱和变化 在生理学上，表明呼吸调节失调。因此，我们假设 MTI 调节 Mtb 的呼吸作用，导致对与呼吸相关的压力敏感，INH 活性增强， 以及 INH 耐药突变体对 INH 的重新敏化，这些都将提高抗生素治疗的疗效， 感染期间的免疫反应。我们已经证明 MTI 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承诺。我们的短期 目标是展示 MTI 对抗 Mtb 感染的临床前概念验证，优化 目前领先的 MTI 转化为治疗药物，并揭示了对药物耐受性和耐药性途径的新见解 反抗。我们的长期目标是开发一种新的口服抗生素，以改善目前的情况 针对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 MTI 通过结构-活性关系 (SAR) 和结构-性能关系 (SPR) 研究。 2） 剖析 MTI 影响 INH 和应激的确切作用方式和详细机制 敏感性。 3) 确定 Mtb 感染期间 MTI 的活性。成功完成这些目标将 导致开发出一种创新的治疗策略来对抗耐药性和耐药性。

项目成果

Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones.

• DOI: 10.1021/acs.joc.1c01875
• 发表时间: 2021-12-03
• 期刊: The Journal of organic chemistry
• 作者: Tyagi M;Adolfsson DE;Singh P;Ådén J;Jayaweera SW;Gharibyan A;Bharate JB;Kiss A;Sarkar S;Olofsson A;Almqvist F
• 通讯作者: Almqvist F

K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones.

K2S2O8 介导的 6-氨基-7-氨基甲基-噻唑啉代-2-吡啶酮与醛的偶联，构建影响嘧啶融合的噻唑啉代-2-吡啶酮的淀粉样蛋白。

• DOI: 10.1039/d1ob01580j
• 发表时间: 2021
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Bharate,JaideepB;Ådén,Jörgen;Gharibyan,Anna;Adolfsson,DanE;Jayaweera,SanduniWasana;Singh,Pardeep;Vielfort,Katarina;Tyagi,Mohit;Bonde,Mari;Bergström,Sven;Olofsson,Anders;Almqvist,Fredrik
• 通讯作者: Almqvist,Fredrik

Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β Fibrils.

• DOI: 10.1021/acs.joc.0c01699
• 发表时间: 2020-11-06
• 期刊: The Journal of organic chemistry
• 作者: Adolfsson DE;Tyagi M;Singh P;Deuschmann A;Ådén J;Gharibyan AL;Jayaweera SW;Lindgren AEG;Olofsson A;Almqvist F
• 通讯作者: Almqvist F

Mycobacterium tuberculosis Rv3160c is a TetR-like transcriptional repressor that regulates expression of the putative oxygenase Rv3161c.

• DOI: 10.1038/s41598-021-81104-y
• 发表时间: 2021-01-15
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Tükenmez H;Sarkar S;Anoosheh S;Kruchanova A;Edström I;Harrison GA;Stallings CL;Almqvist F;Larsson C
• 通讯作者: Larsson C

Understanding the contribution of metabolism to Mycobacterium tuberculosis drug tolerance.

• DOI: 10.3389/fcimb.2022.958555
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7