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进化 许多细菌种类结合在一起作为一个密集的集体，并在表面上迁移， 这个过程叫做swarming。蜂群对一大类抗生素表现出高度耐受性， 让人想起在生物膜和其他环境中看到的耐受性。与后一种环境不同， 然而，当细菌生长速率较慢和代谢活性较低时， 对药物治疗有更高的耐受性，细菌群在代谢上高度活跃， 很强壮因此，蜂群表现出的耐受性显然不同于其他报道的耐受性。 这种现象的案例。我们最近在理解宽容方面取得了重大进展， E.当我们发现菌群的内在程序是上调 多种药物外排泵和保护免受抗生素的ROS途径的表达 应力与此同时，蜂群也下调了与错配有关的基因的表达， 和碱基切除DNA修复途径。与这一观察相一致，初步数据显示， 表明蜂群有更高的突变率， 与抗生素相比，它们对抗生素的耐药性。相关的健身成本 具有较高突变率的基因，显然超过了进化性对遗传的优势。 阻力我们建议研究如何上调外排的内在程序 路径展开。我们还建议研究外排蛋白上调与 下调DNA修复途径。干扰抵抗的进化，因此 宽容，也许与打击抵抗本身同样重要。调查潜在的 耐受机制可能在未来导致基于遗传或生理学的标记， 诊断治疗和根除