Accelerated evolution of antibiotic resistance in a bacterial swarm

细菌群中抗生素耐药性的加速进化

• 批准号: 10377986
• 负责人: Rasika M Harshey
• 金额: $ 19.81万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377986
• 关键词: Address; Affect; Altruism; Antibiotic Resistance; Antibiotics; Bacteria; Bar Codes; Base Excision Repairs; Binding; Case Study; Cells; Cessation of life; DNA Repair Pathway; Data; Diagnosis; Down-Regulation; Drug Efflux; Environment; Escherichia coli; Evolution; Exhibits; Exposure to; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; Incubators; Investigation; Lead; Libraries; Link; Metabolic; Microbial Biofilms; Mutation; Pathway Analysis; Pathway interactions; Pharmacotherapy; Physiology; Process; Proteins; Regulation; Reporter; Resistance; Stress; Surface; Testing; Time; Up-Regulation; antibiotic tolerance; base; commune; cost; efflux pump; experimental study; fitness; gene function; genetic resistance; non-genetic; programs; repaired; transcriptome sequencing

Accelerated evolution of antibiotic resistance in a bacterial swarm Many bacterial species band together as a dense collective and migrate over surfaces in a process called swarming. Swarms exhibit high tolerance to a broad class of antibiotics, reminiscent of the tolerance seen in biofilms and other settings. Unlike the latter environments however, where slower bacterial growth rates and lower metabolic activity are implicated in the higher tolerance to drug treatment, bacterial swarms are metabolically highly active and grow robustly. Thus, the tolerance exhibited by swarms is apparently distinct from the other reported cases of this phenomenon. We made significant recent progress in understanding tolerance in E. coli swarms when we discovered that swarms are intrinsically programmed to upregulate expression of multiple drug efflux pumps and of ROS pathways that protect against antibiotic stress. At the same time, swarms also downregulate expression of genes involved in mismatch and base-excision DNA repair pathways. Consistent with this observation, preliminary data show that swarms have higher mutation rates and are more proficient at evolving genetic resistance to antibiotics compared to their planktonic counterparts. The fitness cost associated with higher mutation rates apparently outweighs the advantage of evolvability to genetic resistance. We propose to investigate how the intrinsic program for upregulating Efflux pathways unfolds. We also propose to investigate the link between upregulation of Efflux and downregulation of DNA repair pathways. Interfering with evolvability to resistance, hence tolerance, is perhaps as important as combating resistance itself. Investigation of the underlying tolerance mechanisms may in the future, lead to genetic or physiology-based markers for diagnosis, treatment, and eradication.

细菌群中抗生素耐药性的加速演变 许多细菌物种作为密集的集体带在一起，并在一个表面上迁移 过程称为蜂群。群体对广泛的抗生素具有很高的耐受性， 让人想起生物膜和其他环境中看到的耐受性。与后一种环境不同 但是，在细菌生长速度较慢和代谢活性较低的情况下与 对药物治疗的耐受性较高，细菌群在代谢上具有高度活性并生长 坚固。因此，群体所表现出的公差显然与其他报道的耐受性不同 这种现象的情况。我们在理解宽容方面取得了重大进展 大肠杆菌群时，当我们发现群体内部编程以上调 可预防抗生素的多种药物外排泵和ROS途径的表达 压力。同时，群还下调了与不匹配的基因的表达 和基本拆卸DNA修复途径。与此观察结果一致 表明群体具有较高的突变率，并且更精通发展的遗传 与它们的浮游物质相比，对抗生素的耐药性。健身成本与 随着较高的突变率显然超过了遗传性的可发展性的优势 反抗。我们建议研究如何上调外排的内在计划 路径正在展开。我们还建议研究外排和 DNA修复途径的下调。干扰了抵抗性的发展性 宽容，也许与打击抵抗本身一样重要。基础调查 耐受机制将来可能会导致基于遗传或生理的标记 诊断，治疗和消除。