Drugs targeting persistent Mycobacterium Tuberculosis

针对持续性结核分枝杆菌的药物

• 批准号: 8822803
• 负责人: WILLIAM Robert JACOBS
• 金额: $ 38.64万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822803
• 关键词: Acute; Address; Adverse effects; Affinity; Antibiotics; Antitubercular Agents; Bacterial Infections; Binding; Biological; Carbamates; Cells; Chemistry; Chronic; Disease; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Drug-sensitive; Evolution; Extreme drug resistant tuberculosis; Funding; Future; Gene Mutation; Genetic Screening; Growth; Health; Humanities; In Vitro; Infection; Laboratories; Lead; Mediating; Microbial Biofilms; Microbial Genetics; Modeling; Multi-Drug Resistance; Mus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; Patients; Pharmaceutical Preparations; Phenotype; Proteins; Proteomics; Research; Resistance; Rifampin; Sterilization; Structure-Activity Relationship; Thiophenes; Time; Tuberculosis; Work; analog; bactericide; base; benzothiazole; burden of illness; chemotherapy; drug development; genome sequencing; global health; high throughput screening; human disease; improved; in vitro Model; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; isoniazid; killings; mouse model; mutant; novel; novel therapeutics; physical property; research study; resistance allele; resistant strain; small molecule; treatment duration; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a devastating bacterial disease for two reasons: First because there are huge numbers involved, approximately 1/3 of humanity is infected, about fifteen million people are in active disease at any one time and about two million die of TB each year. Secondly, TB is one of the most difficult bacterial infections to trea. To treat fully drug-sensitive cases of active TB takes six months and requires four different antibiotics. Multi-Drug Resistant (MDR) and eXtensively Drug Resistant (XDR) TB are resistant to some, or all, respectively, of the first line antibiotics and require drugs that are more dangerous to the patient, often must be given intravenously, and are much more expensive. There is an urgent need for faster-acting antibiotics against TB with fewer side effects and for antibiotics that are effective against MDR and XDR TB. We found that mutants unable to make biofilms are more sensitive to antibiotic in vitro during planktonic growth. Inspired by these results, we hypothesized that in vitro biofilm formation could be a unique phenotype to develop a high-throughput screen for inhibitors with novel mechanism(s) of action. A cell-based screen of 70,000 compounds for molecules that inhibit biofilm formation in Mycobacterium smegmatis yielded a number of compounds that strongly inhibit biofilm formation in Mycobacterium tuberculosis (Mtb). One candidate TCA1 has bactericidal activity against both drug susceptible and drug resistant Mtb and synergizes with rifampcin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition TCA1 showed bactericidal activity against both replicating and non-replicating Mtb in vitro. Furthermore, we have demonstrated that TCA1 is active in a Mtb mouse infection model both independently and in conjunction with INH or RIF suggesting that it is a promising lead for drug development. We propose to characterize the biological mechanism of TCA1 and carry out structure-activity relationship (SAR) studies to improve the potency and pharmacokinetics of this molecule against susceptible and drug resistant Mtb. The result will be robust lead candidates with in vivo proof of efficacy that can be further optimized and developed through future funded collaborative efforts as novel therapeutics for the treatment of TB.

描述（由申请人提供）：结核病（TB）是一种毁灭性的细菌性疾病，原因有二：首先，因为涉及的人数众多，大约有 1/3 的人类受到感染，大约 1500 万人在任何时候都处于活动状态，每年大约有 200 万人死于结核病。其次，结核病是最难治疗的细菌感染之一。治疗对药物完全敏感的活动性结核病病例需要六个月的时间，并且需要四种不同的抗生素。多重耐药 (MDR) 和广泛耐药 (XDR) 结核病分别对部分或全部一线抗生素具有耐药性，需要使用对患者更危险的药物，通常必须静脉注射，而且价格昂贵。迫切需要针对结核病的起效更快、副作用更少的抗生素，以及对耐多药和广泛耐药结核病有效的抗生素。我们发现，无法形成生物膜的突变体在浮游生长期间对体外抗生素更敏感。受这些结果的启发，我们假设体外生物膜形成可能是一种独特的表型，可用于开发具有新颖作用机制的抑制剂的高通量筛选。对 70,000 种抑制耻垢分枝杆菌生物膜形成的分子进行基于细胞的筛选，产生了许多能强烈抑制结核分枝杆菌 (Mtb) 生物膜形成的化合物。一种候选 TCA1 对药物敏感和耐药 Mtb 均具有杀菌活性，并在体外灭菌 Mtb 时与利福平 (RIF) 或异烟肼 (INH) 协同作用。此外，TCA1 在体外对复制型和非复制型 Mtb 均表现出杀菌活性。此外，我们已经证明 TCA1 在 Mtb 小鼠感染模型中既独立又与 INH 或 RIF 联合发挥作用，表明它是药物开发的一个有前途的先导药物。我们建议表征 TCA1 的生物学机制，并进行构效关系 (SAR) 研究，以提高该分子对抗敏感和耐药 Mtb 的效力和药代动力学。结果将是具有体内疗效证明的强大的主要候选药物，可以通过未来资助的合作努力进一步优化和开发，作为治疗结核病的新疗法。