Ambruticins: An inspiration to develop novel biocatalysts and antifungal agents

Biosynthetic studies are providing fascinating insights into genetics and enzymology leading to the prospect of manipulating pathways for the clean and efficient synthesis of bioactive natural products Our goal is to harness the power of biosynthesis not only for the rational manipulation of the pathways themselves to provide new bioactive compounds and biocatalysts, but also as an inspiration to develop new and efficient synthetic strategies to a library of sp3-rich scaffolds of potential value in both crop science and medicinal chemistry.

Ambruticins are polyketide-derived natural products produced by Sporangium cellulosum and they exhibit potent antifungal activity. They are complex with many interesting structural features including nine asymmetric centres, a methyl cyclopropyl group and two oxygen heterocycles. We will investigate key steps of the biosynthetic pathway with the longer-term goal of providing biocatalysts of widespread utility. Furthermore, the first total synthesis of a key proposed intermediate, ambruticin J, will be developed, ideally using a versatile biomimetic strategy which will be adapted to provide analogues of the natural product as potential new antifungal agents.

The students will be the key beneficiaries of this research as they will be exposed to and be able to exploit a new form of
PhD training in the chemical sciences. In particular they will be able to input to and shape their project before embarking on
it - this will make a key impact on the science compared to the normal PhD route and will produce students who are
motivated and engaged from the start. Aspects of the course such as Brainstorming, regular problem sessions, Outreach
and Public Engagement, and the organization and delivery of the CDT-Syngenta Award to a world-leading academic will
produce students who are more confident in their own abilities. This in turn will have a real impact on their future careers
when making presentations or when interviewed, as well as fast tracking their leadership skills. Other aspects of the
training such as IP, Entrepreneurship and Commercialisation, will help stimulate and prepare these students for developing
their own Start-up ventures based around their science skills. Science and Technology SMEs are increasingly vital to the
UK's economy and if we are to make an impact on the world stage our next generation of scientists must be empowered to
move quickly and flexibly in that direction. At an academic level the science that these students will produce will make an
impact right across the chemical synthesis landscape and will train a new generation of academic unafraid to cross
chemical boundaries. These students promise to contribute to vitally important areas of society such as healthcare,
medicine, energy and food production - all requiring new molecular entities to be produced efficiently and effectively. The
nations health both financially (eg GDP) and physically (eg antibiotics) desperately need innovative new directions. For
example, the Pharmaceutical industry requires a new direction for drug discovery. One ripe area is to explore new 3D
molecular space, a space that just a few years ago would have been avoided due to complexity and expense. If new drug
IP is to be created, and tax revenue thereof, then we must train a new generation of molecule makers who are unafraid to
take on the challenges of this unexplored space and, more importantly, be able to exploit it commercially. We believe that
our Centre will be able to train PhD students with this level of scientific skill and commercial aspiration.
Our industrial stakeholders are invaluable to the the patronage and direction of the Centre and will benefit greatly from
direct interaction with the various cohorts during their tenure in the Centre. For example, by providing the CDT students
with industrial placements, an effective two way knowledge and skills exchange will operate: students will get invaluable
insight into small, medium and large industries; industry will see first hand the highly motivated and skilled students the
Centre produces as well as get access to much of the unique electronic teaching material that the Centre has developed.
Finally the CDT will have a positive impact on supervisor behavior by ensuring collaboration under conditions that are not
forced or artificial. All potential PhD projects submitted for Brainstorming must have at least two supervisors. This can be
either academic -academic (home/away) or academic-industrial. We have found with the current CDT that these proposals
must describe real collaborations or the students are unlikely to select them. This provides the right encouragement for
collaborators to generate strong proposals that will interest all parties, which in turn is leading to high quality publications in
high impact journals.