Microbial Synthetic in vivo Cell Therapy Systems

Introduction

Bacteria are among the most brilliant chemists on Earth. They are capable of producing a wealth of structurally diverse natural products with a wide range of applications in medicine, such as the treatment of infections and cancer. The synthetic production of microbial natural products and their transformation into pharmaceutical drugs is often a challenging, costly, and time-consuming process due to the structural complexity of these molecules and the difficulties associated with drug solubility and formulation.

Emerging Strategies

An emerging new strategy in disease treatment aims to exploit beneficial intestinal microbes for ‘local’ drug production and delivery. Such commensal bacteria are safe, can be administered easily, and can be engineered to detect diseases and release drugs in adequate local concentrations.

Current Limitations

However, the current therapeutic platform or ‘chassis’ strains cannot stably colonize the human gut and have so far only been engineered to produce therapeutic proteins, such as hormones or cytokines. As a result, no commensal chassis strains are available to treat chronic intestinal diseases or to produce clinically important natural product therapeutics.

Project Proposal

In MiStiC, I propose to revolutionize microbial therapy systems by developing the beneficial, stable, and prominent gut colonizer Clostridium leptum as an innovative and superior chassis for long-term health monitoring and chronic disease treatment.

Methodology

I will combine my expertise in:

1. Molecular microbiology
2. Enzyme engineering
3. Natural product biosynthesis

to equip the chassis with a nanobody-based biosensor and biocontainment modules, and optimize it for the expression of natural product biosynthetic pathways.

Proof-of-Concept

As a proof-of-concept, we will implement these tools and chassis strains for the detection and treatment of colorectal cancer. Together, these innovations will have broad translational applications and will pave the way to a new frontier in the field of microbiome engineering and synthetic microbial therapy systems.