New Agents for the Treatment on Mycobacteria Avium Infections

治疗鸟分枝杆菌感染的新药

• 批准号: 10482476
• 负责人: Dennis L. Wright
• 金额: $ 30万
• 依托单位: QUERCUS MOLECULAR DESIGN, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482476
• 关键词: ADME Study; Accounting; Airborne Particulate Matter; Animals; Antibiotics; Chimera organism; Clarithromycin; Climate; Clinical; Collection; Development; Dihydrofolate Reductase; Dose; Drug Targeting; Drug resistance; Environment; Environmental Exposure; Enzymes; Evaluation; Folic Acid; Folic Acid Antagonists; Formulation; Genus Mycobacterium; Goals; Grant; Growth; Hematology; Human; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Infectious Skin Diseases; Inhalation; Knowledge; Lead; Libraries; Life; Liposomes; Lung; Lung diseases; Lung infections; Lymphatic; Modeling; Multienzyme Complexes; Mycobacterium Infections; Mycobacterium avium; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium intracellulare; New Agents; Organism; Permeability; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; Preparation; Prevalence; Program Development; Protein Isoforms; Resistance; Resistance profile; Respiratory Tract Infections; Route; Safety; Small Business Technology Transfer Research; Soil; Source; System; Therapeutic; Treatment Cost; United States; Water; Work; alternative treatment; aqueous; candidate selection; clinically relevant; combat; comorbidity; cost; efficacy evaluation; efficacy study; healthcare community; in vitro Model; in vitro activity; in vivo; in vivo Model; in vivo evaluation; lead candidate; mycobacterial; nanomolar; non-tuberculosis mycobacteria; nucleic acid biosynthesis; opportunistic pathogen; pathogen; physical property; preclinical evaluation; product development; public health relevance; safety study; standard of care; therapeutic development; trend

Abstract: Non-Tuberculosis Mycobacteria (NTM) are responsible for widespread, life threatening infections of the lungs, skin, lymphatic and hematological systems. The rapid, global spread of resistant organisms has significantly reduced the number of agents that can be used effectively to treat these infections. Of specific clinical relevance are the slow-growing Mycobacterium avium complex (MAC) comprised of M. avium, M. intracellulare and M. chimaera. MACs are widely distributed throughout the environment, often found in soil, water and airborne particulates. Mycobacterial infections are a growing cause of concern in immunocompromised individuals with underlying comorbidities and represent a significant threat as opportunistic pathogens. Over the past three decades, the incidence of infections caused by MAC NTMs have increased more than 30-fold. Change in the world climate is allowing these once-unknown environmental mycobacteria to flourish and establish themselves as an increasingly common source of deadly infections, accounting for approximately 40% of the pulmonary infections (NTM lung disease) found in immunocompromised patients. Currently in the United States, the prevalence of MAC NTM infections is approximately 50 per 100,000 population, equating to more than 200,000 new cases annually. It is estimated that this number will grow at a rate of +8% per year. The costs associated with treatment of NTM-related infections exceeded $800M in 2018. MAC NTM-LD represents an unmet clinical need as there are few safe and effective drugs available to combat the infections they cause. Furthermore, because standard antibiotics have so much environmental exposure, many MAC isolates are natively drug resistant. QMD is focused on the development of an inhaled therapeutic that inhibits the essential NTM enzyme dihydrofolate reductase (DHFR), which is involved in the biosynthesis of the nucleic acid building blocks that are a key player in the folate cycle and a validated antibiotic drug target.

摘要：非结核分枝杆菌(NTM)可引起广泛的、危及生命的感染 肺部、皮肤、淋巴和血液系统。抗药性生物在全球的快速传播已经 大大减少了可用于有效治疗这些感染的药物的数量。特定的 与临床相关的是由M.avium、M.avium组成的生长缓慢的禽分枝杆菌复合体(MAC)。 细胞内和嵌合体M.Mac广泛分布在整个环境中，通常存在于土壤中， 水和空气中的微粒。分枝杆菌感染日益引起人们的关注。 免疫受损的人，有潜在的合并症，并作为机会主义者构成重大威胁 病原体。在过去的三十年里，由非传染性非传染性疾病引起的感染的发生率增加了更多。 不只是30倍。世界气候的变化正在允许这些曾经不为人知的环境分枝杆菌蓬勃发展 并将自己确立为日益常见的致命感染源，约占 40%的肺部感染(NTM肺部疾病)发现于免疫功能低下的患者。目前在 在美国，非传染性支气管炎的流行率约为每10万人中有50人感染，相当于 每年新增病例超过20万例。据估计，这一数字将以每年+8%的速度增长。这个 2018年，与治疗非传染性疾病相关感染相关的费用超过8亿美元。 Mac NTM-LD代表着一种未得到满足的临床需求，因为几乎没有安全有效的药物可供对抗 它们引起的感染。此外，由于标准抗生素在环境中的暴露程度很高， 许多MAC分离株具有天然的抗药性。QMD专注于开发一种吸入型治疗药物 这抑制了必要的NTM酶二氢叶酸还原酶(DHFR)，该酶参与了 核酸构建块是叶酸循环中的关键角色，也是有效的抗生素药物靶标。