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

抗生素对细菌生长和明确的感染有负面影响，因此它们被用于治疗。因此，人们把重点放在抗生素对微生物生长的早期阶段的影响上，标准化的抗生素敏感性测试仅限于测量几个小时的生长，而感染可能持续数年。我们衡量这些药物对微生物生命和死亡的所有阶段的影响，这是我们理解抗生素治疗的基础。在生活的各个层面上，权衡无处不在，它被定义为当一个特征的有益变化与另一个特征的不利变化联系在一起时，有机体所经历的健康成本。特别是，细菌受到生长和寿命之间的权衡，即生长较慢会导致加速死亡，而快速生长则不利于寿命。某些抗生素故意减慢生长速度，但对细菌寿命的影响尚不清楚。因此，该项目将结合进化实验和全基因组测序，探索抗生素对细菌死亡阶段的影响。最后，有太多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了解有限。使用纳米孔测序，我们将表征患者内部全基因组对慢性感染期间重复抗生素治疗的适应。这将发展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.