Transition-State Analogue Inhibitors of Dihydrofolate Synthetase for MDR/XDR TB

用于治疗 MDR/XDR TB 的二氢叶酸合成酶过渡态类似物抑制剂

• 批准号: 8317529
• 负责人: Joel R Morgan
• 金额: $ 28.07万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317529
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Anabolism; Antibiotic Resistance; Bacteria; Bacterial Infections; Binding Sites; Biochemical; Biological Assay; Carbon; Cells; Coenzymes; DNA biosynthesis; Development; Diet; Dihydrofolate Reductase; Dihydrofolate synthase; Disease; Dose; Dose-Limiting; Drug Delivery Systems; Drug Resistant Tuberculosis; Drug resistance; Enzyme Inhibition; Enzymes; Epidemic; Extreme drug resistant tuberculosis; Fluoroquinolones; Folate; Glutamates; Glycine; Growth; HIV; Health; Human; In Vitro; Injectable; Lead; Life; Malignant Neoplasms; Methionine; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Multiple drug resistant Mycobacteria Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Parasitic infection; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Protein Biosynthesis; Pterins; Purine Nucleotides; RNA chemical synthesis; Reaction; Resistance; Rifampin; Serine; Site; Small Business Innovation Research Grant; Source; Staging; Structural Models; Technology; Testing; Tetrahydrofolates; Text; Therapeutic; Toxic effect; Tuberculosis; analog; antimicrobial; bactericide; base; cofactor; combat; dihydrofolate; dihydropteroate; inhibitor/antagonist; isoniazid; meetings; novel; oxidation; pathogen; resistant strain; therapy development; thymidylate; tuberculosis drugs

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) is a notorious pathogen whose increasing resistance to antibiotics and heightened lethality in combination with AIDS makes it a major health concern worldwide. The selection and spread of multiple drug resistant Mtb continued for decades leading to selection and spread of two operationally distinct forms, multiple drug resistant (MDR-TB) and extensively drug resistant (XDR-TB). The estimate for global MDR-TB and XDR-TB cases for 2007 were 500,000 and 40,000 respectively. Given the worldwide epidemic in tuberculosis and emergence of drug resistant strains, eradicating MDR-TB and XDR-TB using the current armamentarium of antimicrobials is untenable. Thus, the discovery of new types of anti-Mtb drugs acting on novel drug targets with no cross-resistance to any existing drugs is urgently needed to combat MDR/XDR-TB. The potential impact of a new antimicrobial to treat MDR/XDR-TB would be expected to be major, potentially affecting hundreds of thousands of patients. Targeting the folate biosynthetic pathway is an established and proven therapeutic strategy in a variety of diseases including cancer, bacterial infections and parasitic infections. In humans, folate requirements must be met entirely from dietary sources. In contrast, Mtb and other bacteria synthesize folates de novo and have enzymes that catalyze the assembly of folate that are absent from humans. One such enzyme in Mtb is dihydrofolate synthetase (Mtb-DHFS) that catalyzes the addition of glutamate to dihydropteroate (DHP) to produce dihydrofolate (DHF). Accordingly, humans completely lack DHFS, but it is essential for the growth of Mtb. Targeting DHFS is therefore a highly attractive strategy for developing therapy for treating MDR/XDR-TB, because (1) DHFS is not involved in cross- resistance to any existing anti-Mtb drugs, and (2) it is predicted that bacterial sanctuary sites could be effectively sterilized using high doses of a DHFS inhibitor to achieve bactericidal concentrations without causing dose-limiting toxicities to the patient. Based on the known catalytic mechanism and structural models of the catalytic and DHP-binding sites in Mtb-DHFS, it is our hypothesis that we will be able to develop potent and selective transition-state analogue inhibitors. Thus, the two-year experimental plan in this SBIR Phase 1 proposal aims to jumpstart the discovery campaign to identify potent and selective inhibitors of Mtb-DHFS. The hypothesis we will test during the 2-year Phase 1 segment is that based on the known catalytic mechanism and structural models of the catalytic and DHP-binding sites, we will be able to develop potent and selective transition-state analogue inhibitors to Mtb-DHFS.

描述（由申请人提供）：结核分枝杆菌（MTB）是一种臭名昭著的病原体，其对抗生素的抵抗力增加，并与艾滋病结合使用杀伤力提高，这使其成为全世界的主要健康问题。多种抗药性MTB的选择和扩散数十年持续数十年，从而选择和扩散两种不同的抗药性形式，多种耐药性（MDR-TB）和广泛的耐药性（XDR-TB）。 2007年全球MDR-TB和XDR-TB病例的估计分别为500,000和40,000。鉴于全球性结核病流行和抗药性菌株的出现，使用当前抗菌剂的武器群消除MDR-TB和XDR-TB是站不住脚的。因此，迫切需要发现针对任何现有药物的新型抗MTB药物的新型抗MTB药物，以抗击MDR/XDR-TB。新抗菌药物治疗MDR/XDR-TB的潜在影响将是主要的，可能会影响数十万患者。靶向叶酸生物合成途径是在包括癌症，细菌感染和寄生虫感染在内的多种疾病中已建立且已证明的治疗策略。在人类中，叶酸的要求必须完全从饮食来源满足。相比之下，MTB和其他细菌合成了从头开始的叶酸，并具有催化人类不存在的叶酸组装的酶。 MTB中的一种这样的酶是二氢叶酸合成酶（MTB-DHFS），可催化谷氨酸添加到二氢翅目（DHP）中产生二氢叶酸（DHF）。因此，人类完全缺乏DHF，但对于MTB的生长至关重要。因此，靶向DHF是一种开发治疗MDR/XDR-TB治疗的高度吸引力的策略，因为（1）DHFS不参与任何现有的抗MTB药物的交叉抗性，并且（2）可以预测，细菌庇护所部位可以使用DHFS抑制性抑制性抑制性促进性抑制作用，从而有效地灭菌。基于MTB-DHF中催化和DHP结合位点的已知催化机理和结构模型，我们的假设是，我们将能够开发出有效和选择性的过渡态类似物抑制剂。因此，该SBIR 1阶段提案中的为期两年的实验计划旨在启动Discovery运动，以识别MTB-DHF的有效抑制剂。我们将在两年阶段1段中检验的假设是，基于已知的催化机制和催化和DHP结合位点的结构模型，我们将能够开发出对MTB-DHFS的有效和选择性的过渡态抑制剂。