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 许多细菌物种作为一个密集的集体聚集在一起，并在表面上迁移 过程称为蜂群。群体对多种抗生素表现出高度耐受性， 让人想起生物膜和其他环境中看到的耐受性。与后面的环境不同 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，菌群代谢高度活跃并生长 稳健地。因此，群体表现出的耐受性显然与其他报道的不同。 这种现象的案例。我们最近在理解宽容方面取得了重大进展 当我们发现群体本质上被编程为上调时，大肠杆菌就会成群结队 多种药物外排泵和 ROS 途径的表达，以防止抗生素的侵害 压力。与此同时，群体也会下调参与错配的基因的表达 和碱基切除 DNA 修复途径。初步数据与这一观察结果一致 表明群体具有更高的突变率并且更擅长进化遗传 与浮游生物相比，对抗生素具有耐药性。相关的健身成本 较高的突变率显然超过了遗传进化的优势 反抗。我们建议研究上调外流的内在程序如何 路径展开。我们还建议调查外流上调与 DNA 修复途径的下调。干扰抗性的进化，因此 宽容也许与对抗抵抗本身同样重要。底层调查 耐受机制将来可能会导致基于遗传或生理学的标记 诊断、治疗和根除。