Identification cloning and heterologous expression of the abyssomicin C biosynthetic gene cluster

Antimicrobial drug resistance is a growing problem both in the UK and abroad; multi-drug resistant microbes are responsible for hospital- and community- acquired infections and are estimated to cost £1 billion per year in the UK alone. Drug-resistance has developed through the over-use and misuse of clinical antibiotics for the past few decades. This problem has been worsened due to the fact that new antimicrobial compounds have not been forthcoming from the pharmaceutical industry; likely due to a change in research agendas. In order to keep one-step ahead of multi-drug resistant microbes, new antimicrobial are required; clinically significant microbes will not have been exposed to these compounds and so will have not yet acquired resistance. Recently, a novel antimicrobial, abyssomicin C, was identified from a microbe isolate from the Sea of Japan, this compound was shown to be effective at killing multi-drug resistant microbes, including MRSA. In order, to fully realize the potential of this compound, we wish to undertake research aimed at discovering how this marine organism makes abyssomicin C. Once we understand how this compound is made, we can improve production (in order to provide enough material for future clinical research), identify novel chemistry for the production of new novel compounds, and identify other organisms that may produce similar compounds with different activities against multi-drug resistant microbes. We hope that this research will help to provide new antimicrobial compounds for future use in the clinic, helping to prevent the growing problem of microbial drug resistance.

Abyssomicin C is a recently discovered antimicrobial natural product that has a completely novel chemical structure, and is the first natural product inhibitor of the essential shikimate pathway present in bacteria and plants. This compound has been synthesized by groups interested in its use as a new pharmaceutical. However, it is unknown how abyssomicin C is biologically synthesized. This is vital both for improving production yields (for potential commercialization), identifying novel enzymes for use in combinatorial biosynthesis, and for the discovery of new compounds with novel activities within this class of natural product. The project will employ a range of techniques including genomic library sequencing and data mining; cloning and heterologous expression; activity screens; and high-density species microarrays to identify both the abyssomicin C biosynthetic gene cluster in Verrucosispora AB-18-032 (producer strain) and homologues in other actinobacterial species. The proposed research will provided a means to exploit this important compound, providing new avenues to tackle the significant problem of antimicrobial drug resistance. Joint with: BB/E017053/1