The role of Esx-3 in mediating drug resistance

Esx-3在介导耐药性中的作用

• 批准号: 10084640
• 负责人: Tanya Parish
• 金额: $ 46.5万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084640
• 关键词: role; Esx; mediating; drug; resistance

Tuberculosis is a major cause of human suffering worldwide, with 1.8 million deaths and 10.4 million new cases in 2015. Although effective drug regimens for the treatment of TB exist, they are lengthy and involve multiple antibiotics to achieve sterilization and prevent relapse. The current treatment for TB is complex and lengthy requiring a minimum of six months with four drugs for the simplest of cases. It is not clear why drug therapy is so prolonged, although several theories relating to the physiological state of the bacteria have been proposed; these include the existence of drug-tolerant populations during infection, the presence of non-replicating (or slowly- replicating bacilli) and the lack of drug penetration to the sites of infection. Much recent effort has been expended in phenotypic screening to identify new molecular series for drug discovery and development; alongside which a chemical genomics approach has been taken to find novel drug targets using hit compounds identified in these screens. We are interested both in developing novel drugs and in understanding how such drugs work. We have identified a common mechanism of resistance to several, chemically-unrelated series in M. tuberculosis which involves mutation in a type VII secretion system (T7SS). We have identified compounds with interesting biological activities and which appear to work via similar mechanisms, or at least resistance is engendered by the same mechanism. Our proposal aims to determine the mode of action of these compounds. We propose that mode of action is via disruption of metal ion homeostasis with additional downstream effects, which would be a novel mechanism for future drug discovery efforts. We have identified mutations in several components of the Esx-3 T7SS (EccA3, EccB3, EccC3 and EccD3) which confer resistance to three compound series. It is unlikely that the Esx-3 system is the cellular target for these compounds, since mutations were found in four different genes, including one cytosolic protein that would not form part of the complex. Therefore it seems likely that resistance arises from a mechanism distinct from loss of compound-target binding. We propose to take a number of approaches combining microbiology, molecular biology and biochemistry to (i) determine the mode of action of compound series (ii) determine how the Esx- 3 T7SS can mediate compound resistance, and (iii) identify and characterize the targets of each series.

结核病是全世界人类苦难的主要原因，死亡180万，10.4 2015年有百万个新病例。尽管存在有效的结核病治疗药物方案，但 长长，涉及多种抗生素以实现灭菌并防止复发。这 当前对结核病的治疗是复杂而冗长的，需要至少六个月用四种药物 对于最简单的情况。目前尚不清楚为什么药物疗法如此延长，尽管有几个 已经提出了与细菌生理状态有关的理论。这些包括 在感染过程中存在耐药群体，存在非复制（或缓慢地） 复制细菌），缺乏药物渗透到感染部位。 最近在表型筛选中花费了许多努力，以鉴定新的分子序列 用于药物发现和发育；以及化学基因组学方法的旁边 使用在这些筛选中鉴定出的HIT化合物来找到新的药物靶标。我们很感兴趣 在开发新型药物以及了解此类药物的工作原理中。我们已经确定了 对结核分枝杆菌的几种化学无关系列的耐药机制 涉及VII型分泌系统（T7SS）中的突变。 我们已经确定了具有有趣生物学活动的化合物，并且似乎可以通过 相同的机制产生了相似的机制或至少电阻。我们的建议 旨在确定这些化合物的作用方式。我们建议采取方式是通过 金属离子稳态的破坏具有其他下游效果，这将是一种新颖 未来药物发现工作的机制。 我们已经确定了ESX-3 T7SS的几个组件（ECCA3，ECCB3，ECCC3）中的突变 ECCD3）赋予三个化合物系列的耐药性。 ESX-3系统不太可能 是这些化合物的细胞靶标，因为在四个不同的基因中发现了突变， 包括一种不会构成复合物一部分的胞质蛋白。因此似乎很可能 这种抗性是由一种与化合物靶向结合的丧失不同的机制引起的。 我们建议采取多种方法结合了微生物学，分子生物学和 生物化学对（i）确定化合物系列（ii）的作用方式（ii）确定eSX-如何 3个T7S可以介导复合抗性，（iii）识别和表征每个目标 系列。