Identifying Robust Collateral Sensitivity Phenotypes Exploitable in a Clinical Context to Minimise the Emergence of Antimicrobial Resistance

T1 Basic Research - T2 Clinical Research

Antimicrobial resistance (AMR) poses a significant threat to global health. Novel strategies in limiting the emergence of AMR are critically needed. One promising approach involves the exploitation of evolutionary biology, specifically a phenomenon known as collateral sensitivity, whereby changes in sensitivity to one class of antibiotics may occur as a result of mutations leading to resistance to an unrelated class of antibiotics. By utilising sequential antibiotic treatment to select against resistance, trade-offs associated with the preservation of antibiotic resistance mutations can be exploited. For a hypersensitive phenotype to be transferable to a clinical setting, it is imperative to establish its reproducibility and conservation across diverse bacterial strains and genetic backgrounds. However, existing studies have predominantly focused on evolving single strains with multiple antibiotics under single growth conditions, leaving a knowledge gap regarding the robustness of collateral sensitivity networks across different strains and conditions. This project aims to address this gap by identifying 1) laboratory media that results in bacteria evolving to resistance along the same evolutionary pathways as we observe in vivo, and 2) robust collateral sensitivity networks reproducible in different strains and genomic backgrounds. Through a comprehensive approach encompassing adaptive laboratory evolution, susceptibility testing, fitness assessment, and detailed bioinformatic analysis, the potential outcomes include the identification of antibiotic pairs that can be sequentially and interchangeably employed to increase bacterial sensitivity to other antibiotics, with a specific focus on carbapenem-resistant, ESBL-producing Enterobacteriaceae. Gaining a more comprehensive understanding of evolutionary trajectories will inform the development of strategies to combat AMR and improve patient outcomes by allowing clinicians to use proven antibiotic therapy which minimises the emergence of resistance.