The Synthesis Of Substituted Tetramates For Antibacterial Activity

Over the last 20 years, antibiotics have started to become less effective and this has been due to the rapid emergence of antimicrobial resistance (AMR) to antibiotics. The ramifications of AMR will have a massive impact on the sustainability of medicine, potentially setting medicine 'back to the dark ages',2-3 where it is estimated by 2050, AMR will lead to 10 million deaths per annum. More unfortunate is that AMR has coincided with the rapid shortage of new effective antibiotics. This has primarily been due to pharmaceutical companies in recent years struggling to make new antibiotics as a result of poor understanding in the methodology of making new classes of antibiotics, in addition to high costs associated with making new antibiotics. This has led to a drying antibiotic pipeline needed to tackle the rapid threat of AMR. Due to pharmaceutical companies modern drug discovery approach to obtaining new antibiotics so far being relatively unsuccessful, this project will bring about the renaissance of natural product guided synthesis of antibiotics which has yielded fruit in the past and combine this with modern drug discovery programmes to obtain new classes of effective antibiotics. This project will specifically focus on tetramates scaffolds, which offers significant promise, as they have very potent antibacterial activity against a range of Gram-positive and Gram-negative diseases, thus providing an excellent starting point. This project will look to make substituted tetramates and create a large library of tetramate systems, where their antibiotic activity will be evaluate against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) strains, as they are of international interest, and are responsible for a wide range of disease states and resistance to common antibiotics used today. Traditionally, natural product tetramates have been difficult and expensive to make, however, Prof. Mark Moloney's group at the University of Oxford have developed a reliable methodology of obtaining mimics of natural product tetramates from relatively cheap starting materials which can incorporate a wide variety of both diversity and functionality, allowing for structure-activity analysis to be undertaken to better understand how to make tetramates drug-like compounds,
and identify from this, the chemical components necessary for antibacterial activity. Moreover, this project will look to incorporate natural product inspired design with more modern-day drug discovery methodologies such as examining tetramates made for solubility, antibacterial activity and if possible, examine for toxicity and ADME properties. It is believed that harnessing both the advantages of natural product guided synthesis of antibiotics with modern-day drug discovery techniques is the fastest approach to dealing with AMR worldwide. This project falls within the EPSRC Physical Sciences research area, specifically in Synthetic Organic Chemistry.