SIGMA: Small molecule Inhibitors targeting the Genetic determinants of Mutagenesis and Adaptability in Mycobacterium tuberculosis

SIGMA：针对结核分枝杆菌突变和适应性的遗传决定因素的小分子抑制剂

• 批准号: EP/X032817/1
• 负责人: Eachan Johnson
• 金额: $ 164.7万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX032817%2F1
• 关键词: SIGMA; Small; molecule; Inhibitors; targeting

To survive myriad chemical and host stresses, isogenic populations of pathogenic bacteria generate phenotypic variability by (i) developing transient subpopulations with distinct metabolic states, (ii) inducible metabolic remodelling, and (iii) stress-induced mutagenesis. Phenotypic variability fuels the ability of pathogenic bacteria to evolve antibiotic resistance, therefore next generation antibiotic therapies which manipulate phenotypic variability itself would be transformative. However, in clinically significant non-model pathogenic bacteria under infection-relevant conditions, we know little either about genetic determinants of phenotypic variability, or about how to modulate them with small molecules. Phenotypic variability in Mycobacterium tuberculosis causes the signature treatment challenges of tuberculosis, a disease which kills 1.4 million people annually. Therefore, we propose to systematically characterise the genetic determinants of phenotypic variability in M. tuberculosis as well as small molecules which modulate them in order to prototype next generation therapies. We will combine development of new methodology, mycobacteriology, functional genomics, and chemical biology in four aims: 1. to elucidate fine structure of metabolic subpopulations and identify genetic and small-molecule modulators of this fine structure. 2. to identify the comprehensive set of genes essential for metabolic remodelling to survive host-related stress conditions that do not permit growth. 3. to identify genetic and small-molecule modulators of inducible mutagenesis under infection-relevant stress. 4. to investigate three new modes of M. tuberculosis eradication to accelerate its killing, eliminate its antibiotic-tolerant subpopulations, and suppress evolution of resistance.

为了在无数的化学和宿主胁迫下生存，病原菌的同基因群体通过（i）发展具有不同代谢状态的瞬时亚群，（ii）诱导的代谢重塑，和（iii）胁迫诱导的诱变来产生表型变异性。表型变异性促进了病原菌进化抗生素耐药性的能力，因此操纵表型变异性本身的下一代抗生素疗法将是变革性的。然而，在感染相关条件下的临床显著的非模型病原菌中，我们对表型变异的遗传决定因素或如何用小分子调节它们知之甚少。结核分枝杆菌的表型变异性导致结核病的标志性治疗挑战，结核病是一种每年导致140万人死亡的疾病。因此，我们建议系统地研究M.结核病以及调节它们的小分子，以便原型化下一代疗法。我们将联合收割机的新方法学，分枝杆菌学，功能基因组学和化学生物学的发展结合在四个目标中：1。阐明代谢亚群的精细结构并鉴定该精细结构的遗传和小分子调节剂。2.确定代谢重塑所必需的一整套基因，以在不允许生长的宿主相关应激条件下生存。3.以鉴定在感染相关应激下诱导诱变的遗传和小分子调节剂。4.探讨M.根除结核病，以加速其死亡，消除其耐药性亚群，并抑制耐药性的演变。