Metabolomics from Manchester to Madrid

The metabolome, encompassing all small molecules (<3000 Da) within a biological system, represents substrates, by-products, and end products of cellular processes. Positioned downstream of the genome, transcriptome, and proteome, the metabolome is closely linked to cellular phenotype. Thus, studying the metabolome of specific phenotypes can provide insights that other –omics approaches may not fully reveal.

We have demonstrated that there are clear differences in the metabolomes of susceptible and resistant bacteria, and that these differences may be observed within 6 hours. This holds great promise for the future and for reducing diagnostic turnaround times for detecting resistance. Moreover, when we examined the implicated metabolic pathways at a holistic level, we observed similarities to those identified in transcriptomic studies on multidrug-resistant plasmid acquisition. This congruence between methods was not only validating but also made me really start thinking about the underlying mechanisms driving the resistant phenotype.

Whilst there are obvious and direct cellular processes associated with resistance that might alter metabolism, e.g., production of hydrolytic enzymes, subtler changes may also play a significant role in shaping the resistant phenotype. Notably, metabolic reprogramming may offset the fitness costs incurred by acquiring a multidrug-resistant plasmid, and fundamental shifts occurring during clonal evolution enable the acquisition and stable maintenance of these plasmids.

To investigate these phenomena further, I decided to go a little off-piste from my usual analytical chemistry ways by integrating some molecular biology to try and take a closer look. I was pointed in the direction of Dr Álvaro San Millán, whose group has recently developed cutting-edge CRISPR-Cas9 methodology for plasmid curing. With the help of AMI’s Professional Development Support Grant, I undertook a collaborative research placement in Dr San Millán’s lab at the Centro Nacional de Biotecnología in Madrid.

During my month-long placement, I gained hands-on experience with the protocols, learning and applying them to my own bacterial isolates. A month in research really isn’t long, so it was an intense but highly rewarding period. I have never been welcomed into a space so warmly as I was there, and it was fantastic to be around such enthusiastic and hardworking individuals. I really enjoyed the spontaneous brainstorming sessions that came out of it too, it is so easy to get stuck in the same rigid line of thinking when you do the same thing day in and day out, but it’s phenomenal how sharing your research with others from a different field of science can generate so many new ideas for experiments.

Upon returning to the UK, I have continued the work initiated in Madrid. The techniques I learned there would have been almost impossible—or at the very least extremely time-consuming—to master without this invaluable opportunity to learn firsthand. Reflecting on my experience, the interdisciplinary nature of my research has underscored the importance of bridging fields to solve complex problems like antimicrobial resistance. This experience has also reinforced the power of collaboration—working across disciplines and institutions not only accelerates scientific discovery but also fosters personal growth as a researcher. For this, I am deeply grateful to AMI for enabling this collaboration.