Scalable Microbial Metabolite Discovery Through Synthetic Biology

Introduction

The discoveries of microbial secondary metabolites (SM) led to an incalculable impact on human health and lifespan. A large share of the antibiotics, anticancers, and immunosuppressants in use today originate from microorganisms. However, discoveries of SMs of microbial origin through traditional approaches have declined in the past decades, depriving drug pipelines of a key source of bioactive molecules.

Consequences of Decline

The consequences are dire, in particular in the case of antibiotics. Encouragingly, the study of the biosynthetic genes responsible for the synthesis of SMs indicates that the natural repertoire remains vastly underexplored. New ways to access it are enabled by DNA technologies.

Method Development

In particular, untapped biosynthetic genes can be interrogated by transferring them into heterologous hosts. I am developing a method for transfer which fulfills the conditions to unleash theoretically massive economies of scale. Here I propose to multiply the scalability of the current heterologous expression framework and effectively overcome the diminishing returns faced by traditional approaches.

Discovery Platform Implementation

1. In the first axis, I will implement a full-fledged discovery platform, optimized to systematically interrogate novel biosynthetic gene clusters identified bioinformatically from a large collection of soil bacteria.
2. Second, the scale and parallel nature of the heterologous expression setup will be used to better understand the logic of activation of biosynthetic genes, and identify optimal ways to increase activation rates among the large reservoir of conditionally silent biosynthetic genes.
3. Finally, the general strategy will be extended to new fungal and bacterial clades to enable interrogation of their vast potential through scalable heterologous expression.

Overall Aim

Overall, this proposal aims at developing heterologous expression into a major way to discover microbial secondary metabolites and drug leads.