Microbial Adaptation to Antibiotic Treatment Both in the Lab and the Clinic

抗生素对细菌生长和清除感染有负面影响，因此它们被用于治疗。因此，人们关注抗生素对微生物生长早期阶段的影响，标准化的抗生素敏感性测试仅限于测量数小时内的生长，而感染可能持续数年。衡量这些药物对微生物生命和死亡的各个阶段的影响，是我们理解抗生素治疗的基础。权衡在生命的所有尺度上都是普遍存在的，它被定义为当一种特征的有益变化与另一种特征的有害变化相关联时，生物体所经历的适应成本。特别是，细菌受制于生长与寿命之间的权衡，因此，较慢的生长导致加速死亡，而快速生长对寿命有害。某些抗生素有意减缓生长速度，但对细菌寿命的影响尚不清楚。因此，本项目将采用进化实验和全基因组测序相结合的方法，探索抗生素对细菌死亡阶段的影响。最后，有大量的研究调查了实验室环境中微生物对抗生素的适应，但我们对人体内微生物适应的理解是有限的。利用纳米孔测序，我们将描述慢性感染期间患者对重复抗生素治疗的全基因组适应性。这将加深我们对病原体如何在人体内长时间进化的理解，更具体地说，是抗生素耐药性的遗传途径。

Antibiotics negatively effect bacterial growth and clear infection, hence why they are used therapeutically. Consequently, there is a focus on the effects that antibiotics have on the early stages of microbial growth, with standardised antibiotic susceptibility tests constrained to measure growth over hours, whilst infections can last for years. It is fundamental to our understanding of antibiotic treatment that we measure the effects that these drugs have on all stages of microbial life and death. Trade-offs are ubiquitous at all scales of life and are defined as the fitness costs experienced by an organism when a beneficial change in one trait is linked to a detrimental change in another. In particular, bacteria are subject to a growth-longevity trade-off, whereby slower growth results in accelerated death and rapid growth is detrimental to longevity. Certain antibiotics purposefully slow down growth rates, however the impact on bacterial longevity is unknown. This project will therefore seek to explore the effects that antibiotics have on bacterial death phase using a combination of evolutionary experiments and whole genome sequencing. Finally, there are a plethora of studies investigating microbial adaptation towards antibiotics within the laboratory environment, and yet our understanding of microbial adaptation within the human body is limited. Using Nanopore sequencing, we will characterise the within-patient genome-wide adaptation to repeated antibiotic treatment during chronic infections. This will develop our understanding of how pathogens evolve over long timescales within the human body, and more specifically the genetic pathways to antibiotic resistance.