Molecular mechanisms of inherent drug resistance in non-tuberculous mycobacteria

摘要 由非结核分枝杆菌（NTM）引起的感染是重要的临床问题。应对 治疗是令人失望的，慢性感染患者的目标通常是控制而不是治愈 感染这意味着延长抗生素治疗的药物和相关的毒性，往往积累 随着时间虽然已经有相当大的投资在开发新的抗生素用于治疗 结核病，由相关生物结核分枝杆菌（Mtb）引起，其中大多数紧急 治疗在NTM中几乎没有活性。这使得治疗越来越多的NTM病例变得非常重要。 有问题在这里，我们建议使用我们最近开发的工具来研究NTMs并确定机制 使这些病原体对它们固有的耐药性的抗生素重新敏感。我们会用一种新的纸巾 肺部感染的培养模型以及基因方法，以发现和验证 允许在可达到的药物浓度下抑制生长和/或通过现有药物更快速地杀死， 先进的抗菌化合物在结核分枝杆菌。然后我们将探索潜在的生物学 致敏机制，并将这些观察结果扩展到人类感染的更常见原因， 鸟分枝杆菌复合体（Mycobacterium avium complex）我们的目标是确定最好的治疗靶点， 导致细菌清除，即使在缺乏有效的宿主防御的情况下。

Abstract Infections caused by non-tuberculous mycobacteria (NTMs) are substantial clinical problems. The response to therapy is disappointing and the goal for patients with chronic infections is generally to control rather than cure infection. This means extended antibiotic treatment with drugs and associated toxicities that tend to accumulate over time. While there has been considerable investment in developing new antibiotics for the treatment of tuberculosis, caused by the related organism Mycobacterium tuberculosis (Mtb), most of these emergent therapies have little or no activity in NTMs. This has made treatment of the rising number of NTM cases highly problematic. Here we propose to use tools we have recently developed to study NTMs and identify mechanisms to resensitize these pathogens to antibiotics to which they are intrinsically resistant. We will use a new tissue culture model of lung infection together with genetic approaches to find and validate genes and pathways that allow growth inhibition at achievable drug concentrations and/or more rapid killing by existing drugs and advanced antibacterial compounds in Mycobacterium abscessus. We will then explore the underlying biologic mechanisms of sensitization and extend these observations to an even more common cause of human infection, organisms of the Mycobacterium avium complex. Our goal is to determine the therapeutic targets that will best result in bacterial clearance even in the absence of effective host defenses.