Developing functional genomics to elucidate mechanisms of action for antibiotic combinations

<p dir="ltr">The global rise in antibiotic resistance has intensified the urgency for innovative strategies to combat bacterial infections. Antibiotic combination therapy emerges as a promising approach, offering versatility in bacterial killing rates, cellular targets, and resistance mitigation. This thesis delves into the genetic and molecular mechanisms underlying the efficacy of antibiotic combinations, employing transposon-directed insertion-site sequencing (TraDIS) as the primary method. The introduction of ChromoCorrect, an innovative tool developed within this thesis, offers a means to detect and correct chromosomal location bias, ensuring the accuracy of experimental results and preventing false positives and negatives in phenotypic laboratory assays. This thesis uncovers both shared and distinct mechanisms of action and resistance among antibiotics, shedding light on the intricate interplay of bacterial responses. Notably, the synergistic antibiotic combination of trimethoprim and sulfamethoxazole elucidates drastic species-specific responses, emphasising the need for comprehensive research to encompass multiple bacterial species. Additionally, an in-depth exploration of gene fitness responses to various antibiotic combinations provides novel insights into molecular interactions underlying synergy. This thesis marks a significant step forward in understanding antibiotic combination mechanisms, laying a foundation for future research aimed at enhancing our arsenal against antibiotic resistance.</p>