New Agents for the Treatment on Mycobacteria Avium Infections

翻译后摘要：非结核分枝杆菌（NTM）是负责广泛的，危及生命的感染 肺、皮肤、淋巴和血液系统。抗药性微生物在全球的迅速传播 显著减少了可有效用于治疗这些感染的药剂的数量。具体 临床相关性是由M. avium，M. 胞内分枝杆菌和M.奇美拉MAC广泛分布于整个环境中，通常存在于土壤中， 水和空气中的微粒分枝杆菌感染是一个日益关注的原因， 免疫功能低下的个体伴有潜在的合并症，并代表着机会性的重大威胁 病原体在过去的三十年里，由MAC NTMs引起的感染发生率增加了更多 超过30倍。世界气候的变化使这些曾经不为人知的环境分枝杆菌得以蓬勃发展 并成为越来越常见的致命感染源，约占 40%的肺部感染（NTM肺病）发生在免疫功能低下的患者中。目前在 在美国，MAC NTM感染的患病率约为每100，000人50例，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。的 2018年，与治疗非结核病相关感染相关的费用超过8亿美元。 MAC NTM-LD代表了未满足的临床需求，因为几乎没有安全有效的药物可用于对抗 它们引起的感染。此外，由于标准抗生素有如此多的环境暴露， 许多MAC分离物是天然耐药性的。QMD专注于开发一种吸入治疗剂 抑制必需的NTM酶二氢叶酸还原酶（DHFR），该酶参与 核酸构建块是叶酸循环中的关键参与者和经验证的抗生素药物靶点。

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.