A hybrid experimental-modelling study of SOS response-induced filamentation and its effect on bacterial colony growth

SOS 反应诱导的丝状化及其对细菌菌落生长影响的混合实验模型研究

• 批准号: 2600806
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2600806
• 关键词: hybrid; experimental; modelling; study; SOS

Bacterial resistance to antibiotics is a global problem which is already implicated in many deaths by bacterial infection. Bacteria can evolve resistance through mutations mediated by the DNA damage-induced SOS response, which also results in DNA repair and cell division inhibition. Whilst DNA-damaging antibiotics and UV radiation are known to activate the SOS response, it remains unresolved whether other, non-primarily DNA damaging bactericidal antibiotics are capable of inducing the SOS response. SOS-induced cell division inhibition also leads to changes in cell morphology as the cells become filamentous. In some wild type cells, the SOS response is spontaneously induced, leading to variations in mutations and morphology between cells. In this project, we propose a hybrid experimental and modelling approach. Using single molecule tracking, we will examine SOS responses to different kinds of antibiotics by looking at concentration dynamics of the SOS regulator LexA and expression of its coprotease RecA. We will then use measurements of expression of sulA, which is regulated by LexA and codes for the cell division inhibitor SulA, to produce a mathematical model linking LexA dynamics and the cell filamentation phenotype. Finally, we will take measurements of E. coli bending under mechanical forces using microfluidics, and growth rates when undergoing filamentation, and use this to develop an individual-based computational model of bacterial colony growth that implements filamentation. We will then use this model, combined with standard microbiology experiments, to understand the effect of SOS heterogeneity at the population scale.

细菌对抗生素的耐药性是一个全球性问题，已经涉及许多细菌感染导致的死亡。细菌可以通过由DNA损伤诱导的SOS反应介导的突变来进化抗性，这也导致DNA修复和细胞分裂抑制。虽然已知DNA损伤抗生素和紫外线辐射可激活SOS反应，但其他非主要DNA损伤的杀菌抗生素是否能够诱导SOS反应仍未解决。SOS诱导的细胞分裂抑制也导致细胞形态的变化，因为细胞变成丝状。在一些野生型细胞中，SOS反应是自发诱导的，导致细胞之间突变和形态的变化。在这个项目中，我们提出了一个混合实验和建模方法。使用单分子追踪，我们将通过观察SOS调节剂莱克萨的浓度动力学及其辅助蛋白酶RecA的表达来检查SOS对不同种类抗生素的反应。然后，我们将使用苏拉的表达的测量，这是由莱克萨和细胞分裂抑制剂苏拉的代码调节，以产生一个数学模型连接莱克萨动力学和细胞增殖表型。最后，我们将测量E。使用微流体技术在机械力下弯曲的大肠杆菌，以及当经历双折射时的生长速率，并使用此来开发实现双折射的基于个体的细菌菌落生长的计算模型。然后，我们将使用这个模型，结合标准的微生物学实验，以了解SOS异质性在人口规模的影响。