| Project Detail |
Antimicrobial resistance (AMR) is a rising global health threat and rapid evolution of resistance against existing or newly developed antibacterial compounds is predicted to lead to 10 million deaths and $60 trillion of lost economic output by 2050. While resistance-conferring mutations, their inheritance and spread by horizontal gene transfer are increasingly well-studied, our understanding of “pre-resistant” cells’ survival and resilience in the presence of lethal antibacterial doses remains unclear. This proposal is stimulated by recent findings suggesting that the extracellular metabolic environment and metabolic adaptations play an overlooked role in transiently buffering antibiotic lethality and, therefore, increase the emergence of subpopulations of cells and their effective size that supports the evolution of antimicrobial resistance. In this proposal, I will systematically dissect mechanisms at work in subpopulations of “pre-resistant” cells of priority pathogens Pseudomonas aeruginosa and Acinetobacter baumannii that can transiently cope with antimicrobial treatment. I propose to combine my expertise in bacterial physiology with the Ralser Lab’s ultra-fast, massive-scale proteomics and phenomics technologies. I will systematically investigate the metabolic stress response in clinically relevant conditions, and identify the key metabolic and signalling processes that support the survival of subsets of challenged cells upon exposure to major classes of clinically applied antimicrobials. Finally, adaptive evolution experiments combined with CRISPR/Cas9 gene editing will validate causal effectors of identified tolerance mechanisms that precede the appearance of resistance-conveying adaptations. Here, I will acquire technical skills in innovative technologies and the host lab will benefit from my experience in working with pathogenic bacteria. I will lead public engagement efforts and disseminate scientific research outputs on an important global health issue. |
