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The early metabolic stages in the evolution of antimicrobial resistance

Objective

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.

Fields of science (EuroSciVoc)

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2021-PF-01

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Coordinator

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 173 847,36
Address
Chariteplatz 1
10117 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

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