Small Molecule Alanine Racemase Inhibitors as Novel Therapeutics for Tuberculosis

小分子丙氨酸消旋酶抑制剂作为结核病的新疗法

• 批准号: 7159222
• 负责人: KAREN G. ANTHONY
• 金额: $ 17万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7159222
• 关键词: alanine; death; enzymes; isomerase; lead; library; small molecule; tuberculosis

DESCRIPTION (provided by applicant): Once thought to be on the decline, tuberculosis (TB) still remains a major global health problem today. With an estimated 8 million new cases and 2 million deaths annually, TB is the leading cause of death from an infectious disease. This situation is further exacerbated by the emergence of multi-drug resistant form of TB (MDR-TB), which is refractory to treatment by available antibiotics. New anti-tubercular drugs are urgently needed to combat MDR strains of Mycobacterium tuberculosis, a NIAID priority pathogen and the causative agent of MDR-TB. The objective of this proposal is to identify new drug candidates for the treatment of TB in general and MDR-TB in particular. To this end, we propose to identify small molecules that prevent the synthesis of the mycobacterial cell wall, a validated target that is essential for the survival of the bacterium. The specific target is the key bacterial enzyme, alanine racemase. This enzyme catalyzes the racemization of L-alanine to D-alanine, and provides the necessary D-alanine precursor for peptidoglycan synthesis. Using purified alanine racemase enzyme from M. tuberculosis, an existing enzymatic assay will be first optimized for high-throughput screening. The assay will then be used to screen proprietary natural and chemical compound libraries in search of small molecules that inhibit the catalytic activity of this enzyme. Hits identified in this manner will be critically evaluated for their ability to inhibit the growth of M. tuberculosis in culture. Successful completion of this project is anticipated to yield 1 or more compounds for further development as drug candidates for the treatment of TB and MDR-TB in ensuing Phase II studies. Approximately 3 million people die of tuberculosis (TB) every year. About 50 million people are infected with TB bacteria that are not susceptible to available antibiotics. The goal of this research is to develop new antibiotics to treat drug-resistant TB.

描述（由申请人提供）：结核病（TB）一度被认为呈下降趋势，但如今仍然是一个主要的全球健康问题。据估计，结核病每年新增病例 800 万，死亡人数 200 万人，是传染病导致死亡的主要原因。多重耐药结核病（MDR-TB）的出现进一步加剧了这种情况，现有抗生素对这种结核病难以治疗。迫切需要新的抗结核药物来对抗耐多药结核分枝杆菌菌株，它是 NIAID 优先病原体和耐多药结核病的病原体。该提案的目的是确定治疗一般结核病、特别是耐多药结核病的新候选药物。为此，我们建议鉴定阻止分枝杆菌细胞壁合成的小分子，这是细菌生存所必需的经过验证的靶标。具体目标是关键的细菌酶——丙氨酸消旋酶。该酶催化 L-丙氨酸外消旋为 D-丙氨酸，并为肽聚糖合成提供必需的 D-丙氨酸前体。使用来自结核分枝杆菌的纯化丙氨酸消旋酶，现有的酶测定将首先针对高通量筛选进行优化。然后，该测定将用于筛选专有的天然和化学化合物库，以寻找抑制该酶催化活性的小分子。将严格评估以这种方式鉴定的命中物抑制培养物中结核分枝杆菌生长的能力。该项目的成功完成预计将产生 1 种或多种化合物，供进一步开发，作为后续 II 期研究中治疗结核病和耐多药结核病的候选药物。每年大约有 300 万人死于结核病 (TB)。大约 5000 万人感染了对现有抗生素不敏感的结核菌。这项研究的目标是开发新的抗生素来治疗耐药结核病。