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Synthetic Biology

Antibiotics and Metabolism

Synthetic Biology - Engineering bacterial metabolism for a sustainable bioeconomy

We want to produce chemicals with non-growing bacteria

In the ERC funded MapMe project, we engineered E. coli strains that switch between growth and overproduction of metabolites. In a pilot study we designed metabolic switches with temperature-sensitive enzymes and used them to overproduce citrulline (Schramm et al. 2020). The signal for the switch was a temperature shift of 6°C, which is easy to achieve even in industrial-scale bioreactors. Now we used CRISPR and created thermo-switches en masse.

Our current library includes hundreds of thermo-switches, that enable us to control growth of E. coli at the level of every cellular process. We found that with the right thermo-switch E. coli maintains metabolically active for days and produce products like arginine (Schramm et al., submitted).

We want access to sustainable feedstocks

So far we focused on overproduction of amino acids like arginine (Sander et al. 2019), or on production of chemical precursors like glycerol (Wang et al. 2021) using glucose as a feedstock. In collaboration with the Lab of Ron Milo at the Weizmann Institute (Israel), we are now using synthetic CO2-fixation in E. coli to produce such chemicals with CO2 as a feedstock.

We can examine engineered bacteria at the system-level

To engineer bacteria, we need to understand how natural metabolic pathways operate and how we can integrate new ones. To learn regulation of metabolism, we use CRISPR interference to perturb hundreds of metabolic genes and measure the cellular responses at scale (Donati et al., 2021). We have also developed methods to detect interactions between genetic and metabolic networks using metabolomics and transcriptomics data (Lempp et al. 2019).

Antibiotics - Bacterial metabolism influences efficacy of antibiotics

Does bacterial metabolism change the way phathogens respond to antibiotics?

Bacterial metabolism affects antibiotic action, but the underlying mechanisms are largely unknown. We are combining genomics, proteomics and metabolomics to explore mechanisms of antibiotic resistance and antibiotic killing in E. coli and S. aureus. For example, we measured antibiotic resistance of 15,120 E. coli mutants, each with a single amino acid change in one of 346 essential proteins. Resistance mutations in essential genes were drug-specific and affected mostly metabolic enzymes. We observed that most mutations that conferred resistance against the b-lactam antibiotic carbenicillin occurred in genes that are involved in purine nucleotide biosynthesis. These purine-mutations introduced bottlenecks in de novo biosynthesis of nucleotides, which led to low ATP levels. A role of purine metabolism in antibiotic action has been shown by others, and we are currently investigating the molecular mechanisms behind this effect (Lubrano et al., unpublished).

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