Engineering gut microbes for disease detection and drug production

the MiStiC project

September 20, 2023

Developing new drugs is a journey that requires significant resources and knowledge. A promising strategy involves harnessing the power of microbes in so-called microbial synthetic in vivo cell therapy systems to produce natural products with medicinal properties. The MiSTiC ERC (European Research Council) project led by Joleen Masschelein (VIB-KU Leuven Center for Microbiology) investigates the potential of beneficial, human-associated microorganisms to produce complex natural products for chronic intestinal disease treatment. This approach can potentially revolutionize drug development, as it addresses challenges of complexity and scarcity while offering new, sustainable routes to personalized medicine.

Complexity and scarcity

The development of new drugs is a complex and time-consuming process that requires a significant investment of resources and expertise. The majority of our clinical drugs today are derived from microbial natural products. However, one of the main challenges associated with synthesizing natural product drug molecules is their complexity. Natural products often have multiple chemical components that are difficult to synthesize through traditional chemical methods. In addition, natural products are usually produced in low quantities by their natural producers, making it difficult to obtain enough for drug development. In other words, natural compounds with therapeutic potential are often too complex to make from scratch or too scarce to harvest from nature.

Natural compounds with therapeutic potential are often too complex to make from scratch or too scarce to harvest from nature. - J. Masschelein

That’s where microbial engineering comes in. Microorganisms are among the most brilliant chemists on this planet and are capable of making remarkably diverse and complex molecules. A promising approach to drug development therefore involves the use of genetically engineered microorganisms to produce natural product derivatives with important pharmaceutical applications efficiently. This approach can potentially revolutionize drug development by providing a more sustainable and cost-effective way to create complex natural products.

MiSTiC

In the ERC project MiSTiC , the team of Joleen Masschelein wants to go one step further by engineering beneficial gut microbes for ‘local’, in situ drug production and delivery. Relying on our own bacteria has several benefits. Commensal bacteria can be administered easily, such as via probiotics, and they do not elicit an immune response. They can deliver drugs to remote sites in the human body that are otherwise difficult to reach, and they can be engineered to produce compounds simultaneously and release drugs in adequate local concentrations causing limited or no side effects.

The Masschelein lab is specifically investigating commensal Clostridium bacteria for long-term, targeted treatment of chronic intestinal conditions. These bacteria – which naturally reside in the human gut – have a native ability to encode natural product biosynthetic machinery, making them a promising candidate for this type of therapy.

Targeted treatment

Another advantage of engineered microbial systems is the potential for targeted treatment of chronic intestinal disorders. Microorganisms can be engineered to detect disease-associated molecules with a high degree of sensitivity and selectivity, and to respond by switching on the expression of therapeutic genes. Restricting drug production to the site of disease is crucial from a biosafety point of view as it reduces off-target toxicity, resistance development, as well as other adverse effects.

In MiSTiC, the team of Joleen Masschelein wants to install a nanobody-based biosensing platform in commensal Clostridia to detect the presence of colorectal cancer cells. These synthetic receptors will not only allow the Clostridium bacteria to bind to colorectal cancer cells, but will also trigger the production of a natural product anti-cancer agent.

Finally, kill mechanisms will be installed that that will eliminate the engineered bacteria when they are no longer required or when they escape into the environment. Having control over the viability of the engineered Clostridia will be crucial for enhancing overall biosafety and biocontainment.

Standing challenges

The use of microbial synthetic in vivo cell therapy systems for drug development is still in its initial stages, but the potential benefits are clear. Using genetically engineered commensal microorganisms to produce therapeutically relevant natural products paves the way towards a more efficient, cost-effective and sustainable drug development process.

However, two major challenges remain.

One of the main challenges is the need for a better understanding of the biosynthetic pathways involved in producing natural products. By better understanding these pathways, it will be possible to engineer microorganisms to produce natural products with greater efficiency and specificity.

Another challenge is the need for better tools and techniques for the genetic engineering of microorganisms. While considerable progress has been made in this area, there is still a need for more efficient and reliable methods for introducing genes into microorganisms and controlling their expression.

The researchers who are part of the MiSTiC project are ready to take on those challenges and develop microbial synthetic in vivo cell therapy systems as an innovative avenue for drug development. The prospect of generating specialized metabolites has profound pharmaceutical implications that may redefine drug development by making it more streamlined and economically viable to produce intricate natural compounds.