A New Front in the War on Superbugs: Synthetic and Biological Studies on the Potent Antibiotic Anthracimycin

Bacterial infections are becoming increasingly hard to treat with current antibiotics and it is well recognised that new treatments are required. The government and the WHO continue to highlight the development of new antibiotics as an area of high priority. However; the pharmaceutical sector is poorly placed to develop these due to the low commercial return on antibiotics of last resort. Anthracimycin is a newly discovered polyketide with potent Gram +ve antibiotic activity, and is especially active against the anthrax pathogen and MRSA. Significantly, given the emergence of ESBLs, the chlorinated anthracimycin analogue, which was prepared from anthracimycin, was found to be active against Gram -ve bacteria, and both molecules were shown to exert their activities via an unknown mode of action which inhibits DNA/RNA synthesis in the bacteria. A related natural product chlorotonil A has also been reported and synthesised but its antibiotic activity has not been disclosed. The importance and urgency of developing new antibacterial agents as treatments of last resort cannot be overstated, and the discovery of anthracimycin provides a new, exciting and timely opportunity to do this. This proposal will build on our previous EPSRC-funded work in the area of the synthesis of natural products active against MRSA (EP/F005970) and seeks to rapidly respond to disclosure of anthracimycin and establish a leading presence in the field of developing these molecules as antibiotics of last resort. This project brings together experts in natural product synthesis and microbiology and aims to develop a chemical synthesis of anthracimycin, chlorinated anthracimycin analogue and chlorotonil A and then elucidate the mechanism by which they exert their antibiotic activity. The project's focus on synthesising these molecules and in expanding the potential of this novel polyketide to function against Gram -ve bacteria aligns it with the healthcare technology challenge theme and especially the associated novel treatment and therapeutic technologies proposed "grand challenge".

Who will benefit from this research?
The development of a new synthetic route to these antibiotic natural products and the elucidation of their mode of action will primarily benefit those in industry and academia engaged in medicinal chemistry and the development of new antibiotics, as it will facilitate the synthesis of novel structures for evaluation as antibiotics and determine new mode of antibiotic action which can be targeted by medicinal chemists. The PDRAs will benefit from this work as they will become trained in modern synthetic and microbiological techniques and gain the skills needed for gainful employment in the UK pharmaceutical industry. Patients suffering from hospital acquired infections will benefit from the use of any new treatments which ultimately arise from this work.

How will they benefit from this research?
The way in which academic groups will benefit from this research are fully detailed in the Impact Plan. In addition, these studies will provide new information on the biological target inhibited by these compounds, which will help in the development of new antibiotics, which would extend and enhance the quality of life. Examples of these have been given in the case for support as well as the impact statement. We also believe that UK/EU industry will be able to gain a commercial advantage as a new biological target is established and validated. The PDRAs associated with this project will be trained in all modern synthetic and microbiological/biochemical techniques, and thus will be a position to enter and contribute to the UK chemical industry. The shadowing period will give both PDRAs a real opportunity to work in the other's environment for 1 month and gain a first hand understanding of research in another related, but distinct, scientific discipline. Fuller details of this aspect can be found in the Academic Beneficiaries section and the Full impact Plan which companies this proposal.

What will be done to ensure that they benefit from this research?
Firstly, the results will be published in high profile international academic journals. We will ensure that our work is published as open access articles in order to allow interested lay-persons and the media free access to the results as well as those scientists with academic subscriptions. Secondly, the results will be disseminated at high profile international conferences. Our ongoing collaborations with industry and other bioscientists will ensure that they are kept abreast of the exciting developments. In addition to these methods of increasing impact, direct contact with the media and publication of articles in national magazines like Chemistry World and Chemistry Review will also be undertaken. The PI and CI have several contacts in the local and national broadcast and print media, which will enable the results obtained to have a wider impact amongst the general public, and these have been detailed fully in the impact plan. York chemistry and biology have a significant presence on Youtube and Twitter and this can be used to ensure the results of the research impacts on the wider online community worldwide. Both departments are fully engaged in outreach initiatives in local schools (in collaboration with the CIEC unit) and this provides an ideal opportunity to enthuse the next generation of young scientists through our work. Where appropriate the intellectual property resulting from this work will be legally protected by the university's dedicated team of IP experts. The PI has a track record here as he has previously protected valuable intellectual property associated with anti-cancer Taxol analogues (US Patent US 6,191,287 B1, Feb 20, 2001).