Drugs targeting persistent Mycobacterium Tuberculosis

描述(申请人提供)：结核病(TB)是一种毁灭性的细菌疾病，原因有两个：第一，由于涉及的人数巨大，大约三分之一的人类被感染，任何时候都有大约1500万人处于活动性疾病中，每年约有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。治疗完全对药物敏感的活动性结核病需要六个月的时间，需要四种不同的抗生素。多药耐药(MDR)和广泛耐药(XDR)结核病分别对部分或全部一线抗生素耐药，需要对患者更危险的药物，通常必须静脉给药，而且价格要昂贵得多。迫切需要副作用更少、作用更快的抗结核抗生素，以及对耐多药和广泛耐药结核有效的抗生素。我们发现，在浮游生长过程中，不能形成生物膜的突变体在体外对抗生素更敏感。受这些结果的启发，我们假设体外生物被膜形成可能是一种独特的表型，以开发一种高通量筛选具有新作用机制的抑制剂(S)。对70,000种化合物进行细胞筛选，筛选出抑制耻垢分枝杆菌生物膜形成的分子，产生了一些强烈抑制结核分枝杆菌生物膜形成的化合物。一个候选的TCA1对药物敏感和耐药的结核分枝杆菌都有杀菌活性，并与利福平(RIF)或异烟肼(INH)在体外杀灭结核分枝杆菌方面具有协同作用。此外，TCA1对复制型和非复制型结核分枝杆菌均具有体外杀菌活性。此外，我们已经证明TCA1在Mtb小鼠感染模型中是独立的，并与异烟肼或RIF联合使用，这表明它是一个有希望的药物开发的先导。我们建议对TCA1的生物学机制进行表征，并开展构效关系(SAR)研究，以提高该分子对敏感和耐药结核分枝杆菌的效力和药代动力学。其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。

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.