The plant IPCS as a novel herbicide target

Intensive agriculture is required to provide sufficient food from a diminishing land bank to feed and fuel a growing world population. In this context, crop protection methodologies, including the use of herbicides to control weeds play an important role and the evolution of herbicide resistant weeds represents a major threat to modern agriculture. Resistance often becomes a problem because of high selection pressure as a result of repeated use of herbicides with the same site of action. Whilst such pressures can be alleviated by crop and herbicide rotations the pool of permitted herbicides is decreasing and there is a major need for new modes of action.
Recent work at Durham University has shown that inositol phosphorylceramide synthase (IPCS), an enzyme involved in sphingolipid biosynthesis, may represent a new herbicide target. Orthologues from Arabidopsis thaliana and rice were isolated and characterized at Durham and a medium throughput screen of 10,000 compounds was performed at BAYER, Frankfurt. From this screen we were able to identify several interesting lead structures with both in vitro and in vivo activity.
This project will build upon these results by using a combination of molecular biology, enzymology, synthetic chemistry and omic technologies to further explore IPCS as a new mode of action for novel herbicides. More specifically, we aim to achieve the following:
Genetic validation of IPCS as a herbicidal target Show that the herbicidal and biochemical activities are related though metabolomic and lipidomic profiling Establish SAR by screening close analoges of hits and synthesise new structures to improve inhibitor potency and herbicidal efficacy (and to minimize cytotoxicity).