THE BAKSHI Laboratory of Systems and Synthetic Microbiology
We are interested in reverse engineering (systems microbiology) and forward engineering (synthetic microbiology) biological networks (gene-regulatory networks and microbial eco-systems) for fundamental and applied reasons. A major focus in our current research is to understand and combat antibiotic resistance and tolerance in microbes. We are using a combination of advanced experiments and modelling to understand these processes in model microbes, and engineering modified microbes to fight back in natural contexts. We effectively combine and use existing methods, and develop new ones when the existing ones fail. Please see below for more details.
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 the cell, which determines the reachability of drug targets, their numbers, and activity. 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, in conjunction with their dynamic relationship with the environment, influence antibiotic efficacy and the emergence of persistent cells, ultimately triggering the spread of resistance. We utilise high-throughput time-resolved imaging to phenotype individual cells, followed by the retrieval of selected cells for genotyping. This generates a wealth of genotype-phenotype data that links genetic makeup to physiological dynamics and connects physiological history to response dynamics. Our methodology involves model-driven experiments and data-driven models to characterise and analyse the systems of interest. This comprehensive approach holds the promise of breakthroughs in the battle against infectious diseases.
How can we develop synthetic biology approaches to resurrect susceptibilities towards existing antimicrobials? How can we harness nature's arsenal against drug-resistant pathogenic cells? How can we apply synthetic biology tools and precise assays to optimise natural machinery for reliably and robustly eliminating resistant infections?
Our approach involves developing methods to identify potent antimicrobials from nature using the systems analysis described above. We specifically focus on tapping into the natural immune systems of the human body and the microbiome. We are advancing on-chip directed evolution and time-resolved screening methods to enhance the performance of identified antimicrobials. This systematic approach aims to unlock the full potential of nature in the ongoing battle against drug-resistant pathogens.
A significant focus in our current research is the exploration of effective bacteriophages from nature and the tailored engineering of phages for specific applications. We have pioneered the development of the first platform for time-resolved phenotyping of bacteriophages to precisely quantify their effectiveness at the single-cell level and screen natural isolates and engineered libraries.
"Measure what is measurable, and make measurable what is not so." - Galileo
We are developing new approaches and tools in molecular biology, microfluidics, microscopy, and machine-learning, and combining them in novel ways to study the gene-expression and physiology of microbes at different levels (single molecule, single cell, population) and designing software 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.