The recently-discovered methylerythritol phosphate (MEP) pathway produces isoprenoids in plant plastids and most microorganisms. Its absence in animals makes it a promising target for antibiotic development. In addition, many isoprenoids have important industrial applications (pharmaceuticals, nutriceuticals, fuels, rubbers, etc.). In order to fully exploit this pathway as a drug target and successfully engineer isoprenoid bioproduction, we must understand its regulation. Emerging disciplines like systems biology, synthetic biology, and computational modelling offer powerful tools to address this problem. However, combined expertise in these disciplines is available in few places in the world.
The first objective is to study carbon flux through the MEP pathway using systems and synthetic biology. This will enable a detailed understanding of the complexity of regulation in the context of the whole metabolic network. Moreover, it will provide engineering targets to improve flux through the pathway (which thus far has met with little success). Targeted engineering will be linked to bio-production of carotenoids, essential isoprenoid nutrients associated with protection against chronic human diseases.
The second objective is to target deoxyxylulose reductase (DXR), a key enzyme that represents a species-specific variant pathway node. The metabolic conseqeunces of this variant node for pathway flux will be examined. Moreover, structural analysis will be used to develop DXR-specific drugs. Indiscriminate use of antibiotics has led to a general decline in their efficacy, and availability of new antibiotics is desperately needed; this approach promises a route to powerful, species-specific antibiotics with fewer side-effects.
It is expected that this research will lead to the generation of fundamental knowledge about the MEP pathway regulation and antibiotic development. This will have wide-reaching applications in biotechnological production of isoprenoids and health.
Call for proposal
See other projects for this call