The evolutionary biology of antibiotic resistance. (360G-Wellcome-106918_Z_15_Z)

Antibiotic resistance poses a growing threat to human health. Natural selection drives the spread and maintenance of antibiotic resistance, but most of our understanding of the evolution of resistance comes from simple in vitro experiments and animal models. My project will bridge the gap between clinical microbiology and evolutionary biology by elucidating the evolutionary processes that drive the spread and maintenance of antibiotic resistance in clinical populations of pathogenic bacteria. Ul timately, this research will contribute to the development of improved methods for mitigating the spread of resistance. Key Objectives: 1. To determine the impact of antibiotic use on bacterial population structure and genetic diversity. 2. To determine if resistance evolves by selection on (i)standing or (ii)novel genetic variation. 3. To estimate the fitness cost of resistance following antibiotic treatment. 4. To determine the rate of compensatory evolution in resistant lineages. 5. T o determine the impact of (i) competition, (ii) immigration and (iii) reversion on the loss of resistance. 6. To determine the genomic basis of resistance evolution. We will study resistance evolution using natural experiments where longitudinal samples of important pathogens (S.aureus and P.aeruginosa) have been obtained from individual patients pre and post exposure to antibiotics. To study evolutionary responses to antibiotics, we will use a combination of whole-genome sequencing and phe notypic assays (resistance, competitive ability, virulence) on individual isolates. In vitro experiments and genetic manipulation will then be used to further investigate the phenotypic and evolutionary consequences of observed changes in the clinical samples.