Abstract

Student name: Lindsay Pike

Thesis title: Characterising antibiotic susceptibility and resistance in human commensal gut bacteria

The human commensal gut microbiota can act as a reservoir of antimicrobial resistance genes that can persist and spread to pathogens. However, the extent and diversity of antibiotic resistance encoded by human commensal bacteria remains to be determined. Due to immediate clinical relevance and our previous inability to culture these commensal bacteria, the majority of research into antibiotic resistance has focused on pathogenic organisms or well-characterized antibiotic resistance mechanisms. Here, I demonstrate the existence of unpredicted antibiotic resistance, not detected by several genome-based prediction methods, in diverse bacterial species from the human gastrointestinal tract.

178 antibiotic resistance genes and mutations were identified in a culture collection of 737 phylogenetically diverse gut bacteria from healthy humans. Recent developments in culturing anaerobic gut bacteria were used to determine antibiotic sensitivity phenotypes and observe the spectrum of clinically relevant antibiotics across the diversity of these isolates. These data were combined to assess the accuracy of genome-based predictions in human commensal gut bacteria, revealing multiple instances of unpredicted antibiotic resistance. This highlights the importance of combining computational genomic prediction with functional validation and increases our knowledge of antibiotic resistance in commensal human gut bacteria.

In addition, the impact of therapeutic amoxicillin treatment on antibiotic resistance in mice with human-derived gut microbiota was studied. These experiments model processes in humans and reveal community- and strain-level changes in antibiotic resistance following antibiotic therapy. These experiments further elucidate the role of the gut microbiota as a reservoir of antibiotic resistance and the influence of antibiotics on this reservoir.