Laboratory of Systems and Synthetic Microbiology

Why do many promising antimicrobials ultimately prove ineffective? Why do a subset of cells persist after treatment, leading to recurrent infections? What sparks resistance in pathogenic cells against current treatments? 

The key lies in the physiological context of cells, which determines the number, activity, and reachability of antimicrobial targets. Cellular physiology varies widely in a population, influenced by intricate interactions with the environment and neighbouring cells.  We are developing a systems approach to understand how physiological heterogeneities of cells, coupled with their dynamic relationship with the environment, influence antibiotic efficacy and trigger the spread of resistance. Our methodology involves model-driven experiments and data-driven models. 

How can we effectively identify potent therapeutic phages from nature and engineer effective therapeutic phages with well-defined functions? How does the physiology of target bacterials cell affect the efficiency of bacteriophages and the coevolution of phage-bacteria systems? 

A significant focus in our current research is the exploration of effective bacteriophages from nature and the tailored engineering of phages for therapeutic applications. A crucial aspect of this work involves the accurate evaluation of phage properties and the comparison of multiple variants under standardized conditions. To address this, we have spearheaded the development of a microfluidic assay capable of providing time-resolved phenotypic assessments of bacteriophages at the single-cell level. Currently, we are in the process of adapting this innovative assay for high-throughput evaluation of both natural isolates and engineered libraries of phages, in terms of their dynamic infection profiles.

How can we harness nature's arsenal against drug-resistant pathogenic cells? How can we apply synthetic biology tools and precise characterisation assays to optimise these natural machinery for reliably and robustly eliminating resistant infections? 

Our approach involves tapping into the natural immune systems of the human body and the microbiome to identify potent antimicrobials. We employ time-resolved characterisation of their activity under complex controlled conditions. We are also advancing on-chip directed evolution and time-resolved screening methods to enhance the performance of identified antimicrobials. We effectively combine and use existing methods, and develop new ones when the existing ones fail (see below). 

"Measure what is measurable, and make measurable what is not so." - Galileo

We are developing new approaches and tools in molecular biology, single-cell microfluidics, high-throuhgput timelapse microscopy, and combining them in novel ways to study physiological dynamics of microbes at different levels (individual cells to populations) and designing software (and machine-learning based image processing and feature identifications) to extract meaning information from these data. We iteratively use computational modelling to interpret the observations and to predict testable outcomes, and use experiments to refine and refute these predictions.