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 许多细菌物种以密集的集体形式结合在一起，并在表面上以 这个过程叫做蜂拥而至。蜂群对多种抗生素表现出高度的耐受性， 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，较慢的细菌生长速度和较低的代谢活动与 对药物治疗的耐受性更高，细菌群在新陈代谢方面高度活跃并生长 很强健。因此，蜂群表现出的耐受性显然与其他报道的不同。 这种现象的案例。我们最近在理解耐受性方面取得了重大进展 当我们发现蜂群在本质上被编程为上调时，大肠杆菌蜂拥而至 多个药物外排泵和抵抗抗生素的ROS通路的表达 压力。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。与这一观察结果相一致，初步数据 表明蜂群有更高的突变率，更擅长进化基因 与浮游生物相比，对抗生素的抗药性。与之相关的健身成本 更高的突变率显然超过了遗传进化的优势 抵抗。我们建议调查内部程序如何上调外流 小路就展开了。我们还建议研究Efflux上调和 下调DNA修复途径。干扰抗药性的进化，因此 宽容，或许与对抗抵抗本身一样重要。对潜在原因的调查 未来，耐受机制可能会导致基于遗传或生理的标记 诊断、治疗和根除。