Project No. 2429
Dr Jennifer Hiscock- University of Kent
Dr George Williams – University of Southampton
Dr Charlotte Hind – UKHSA
Antimicrobial resistance (AMR) has now been identified to every antibiotic currently marketed.
The unmet need: Antimicrobial resistance (AMR) has now been identified to every antibiotic currently marketed. By 2050, it is predicted that deaths attributed to AMR will be greater than those currently attributed to cancer however, these predicted numbers did not take into account the global increase in the use of antimicrobial agents during the COVID-19 pandemic, reported to have further exacerbated the rise of AMR – which is now termed by some as the ‘silent pandemic’. Inin 2019 it was established that more people died from the primary effects of AMR infection the malaria or AIDS.
This means that the development of novel antibiotics, or ways of increasing the efficacy of known antibiotics, to which there is resistance, is of the highest global importance.
The project: In 2016 Jennifer Hiscock (main supervisor) invented a novel class of molecules, supramolecular self-associating amphiphiles (SSAs). This technology has subsequently been developed into a patented therapeutic platform technology, containing >150 molecules that have been shown to act as both antimicrobial agents (MIC = 4 µg/mL) and efficacy enhancement agents for known antibiotics against both Gram positive and negative bacteria at therapeutically relevant concentrations. The selectivity and activity of SSAs is due to our ability to tune the molecular structure to selectively interact, and subsequently permeate a cell membrane of a desired phospholipid composition. More excitingly, lead SSAs have demonstrated druggable profiles when administered intravenously to mice, meaning that these molecules really do demonstrate the potential to be developed into next generation antibiotics/antibiotic enhancement agents for use in the clinic. However, further technological developments are still necessary before this can happen.
This project will address a key SSA translational roadblock: how to enhance SSA antimicrobial activity and microbial selectivity to enabling identification of next-generation SSAs that we will develop together as lead clinical candidates.
Here you will incorporate photoswitches into the SSA structure for the first time, enabling the adjustment of molecular membrane interactions in situ, through irradiation with light. This will enable us to simultaneously increase SSA efficacy and control system activity or microbial selectivity in real time. These compounds will be synthesised, characterised and their antimicrobial activity/mode of action elucidated using our published and well-established methods, in addition to state-of-the-art in situ NMR irradiation techniques.
Project skills: During this project you will gain skills in the following areas which include, but are not limited to: chemical synthesis; microbiology; microscopy, NMR spectroscopy; mass spectrometry; single crystal X-ray diffraction; molecule-biological membrane assay development; photochemistry; pharmacokinetics.
PhD candidate profile: We are looking for a candidate with experience in microbiology or chemistry, with a passion to work at the interface of multiple scientific disciplines and excellent communication skills, as this project will involved working with the wider SSA development consortia to progress this innovation towards the clinic.