New Agents for the Treatment on Mycobacteria Avium Infections

治疗鸟分枝杆菌感染的新药

• 批准号: 10597233
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597233
• 关键词: ADME Study; Accounting; Airborne Particulate Matter; Animals; Antibiotics; Antimycobacterial Agents; Biological Availability; Chimera organism; Clarithromycin; Climate; Clinical; Collection; Development; Dihydrofolate Reductase; Dose; Drug Targeting; Drug resistance; Environment; Environmental Exposure; Enzymes; Equation; 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; 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; liposomal formulation; 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：无结核病分枝杆菌（NTM）负责广泛的，威胁生命的感染 肺，皮肤，淋巴和血液系统。抗性生物的快速，全球传播具有 显着减少了可有效用于治疗这些感染的药物的数量。具体 临床相关性是由M. avium，M。组成的缓慢生长的分枝杆菌（MAC）。 ellacelulare和M. Chimaera。 Mac广泛分布在整个环境中，通常在土壤中发现， 水和空气颗粒。分枝杆菌感染是越来越关注的原因 免疫功能低下的人具有潜在的合并症，并代表了机会主义的重大威胁 病原体。在过去的三十年中，由Mac NTM引起的感染发生率增加了 超过30倍。世界气候变化使这些曾经不知名的环境分枝杆菌蓬勃发展 并将自己确立为致命感染的日益普遍的来源，约占 在免疫功能低下的患者中发现了40％的肺部感染（NTM肺部疾病）。目前在 美国，Mac NTM感染的患病率约为每100,000人口50个，相当于 每年有200,000多个新案件。据估计，这个数字每年将以 +8％的速度增长。这 与NTM相关感染的治疗相关的成本在2018年超过8亿美元。 Mac NTM-LD代表未满足的临床需求，因为很少有安全有效的药物可供战斗 它们引起的感染。此外，由于标准抗生素具有太多的环境暴露，因此 许多MAC分离株具有耐药性。 QMD专注于吸入治疗的发展 抑制必需的NTM酶二氢叶酸还原酶（DHFR），该酶涉及的生物合成 核酸的构建块是叶酸周期中的关键参与者和经过验证的抗生素药物靶标。