A Synthetic Biology Platform for Rapid Generation of Highly Diverse Natural Product-Like Compounds Active Against Mycobacterium tuberculosis
Michael Tyers of the University of Montreal in Canada will develop a synthetic biology platform to generate vast libraries of natural product-like compounds and use them to identify new drugs for tuberculosis. Traditional drug discovery screens require expensive chemical libraries that are limited in size and scope. Many existing drugs are derived from the natural products of microbes which perform a wide variety of biological functions. This functional diversity is reflected by their structural diversity which is generated by the combinatorial action of hundreds of thousands of different enzymes. They will exploit this natural manufacturing process for the relatively simple and low-cost production of millions to billions of chemically-diverse natural product-like compounds. This will be achieved by expressing different combinations of the enzymes in yeast artificial chromosomes which then allows screening directly in the yeast without the need for costly and time-consuming chemical extraction and purification. Using this approach they will perform a pilot screen to identify new compounds that inhibit the growth of the bacterium that causes tuberculosis.