The goal of my PhD will be the discovery and improvement of novel antibiotics by refactoring their cognate biosynthetic gene clusters via synthetic biology approach.

More information about Chaoxian Bai

Since brute force natural products (NPs) discovery does not yield the same result as it did in the past, we need to find a way to access the NPs lie hidden in the genomes of bacteria. Antibiotics are molecules that likely play a role in survival in a competitive environment, which has radically different from that in the laboratory. We therefore need to elucidate the triggers and cues that activate the expression of BGCs, and harness these to develop new drug-discovery approaches. Another way of exploiting the rich chemical diversity is to mine microbial genomes for promising BGCs and clone or even synthesize them followed by expression in heterologous production hosts. Since DNA from microbial communities in e.g. soil or sediments can be directly extracted and sequenced, this circumvents the problem that the vast majority of microbes cannot be cultivated in the laboratory. 

During my MSc, I co-established a precise quantitative method based on flow cytometry and fluorescent protein at single-cell resolution in streptomycetes. We then developed and characterized hundreds of regulatory elements (e.g. promoters, Ribosome Binding Sites) by this method. These artificial regulatory elements were successfully applied in a proof-of-principle approach to activate and overproduce the cryptic lycopene gene cluster from Streptomyces avermitilis. Native BGCs are subject to complex regulation, which makes them often difficult to activate in the laboratory. Due to the interactions within the cellular and extracellular context, novel approaches are required for more predictable and reproducible expression of such BGCs. This PhD project will develop and deploy novel strategies to activate cryptic BGCs and identify their cognate NPs.