While antibiotics have revolutionised the landscape of medicine saving millions of lives, their misuse has also resulted in the rise of “Superbugs”, which are bacteria resistant to most of the standard antibiotics. Each year worldwide the number of people dying as infected with superbugs is alarming increasing. This project proposes to develop novel antimicrobials that target bacterial cell division, a crucial step for bacterial replication and survival. We will combine our expertise in medicinal chemistry and microbiology to design molecules that, acting like “Trojan horses”, cross the bacterial cell envelope and once inside become toxic and kill the bacteria. Could nucleotide Ftsz inhibitors be developed as antibiotics to fight AMR? Due to its essential role in bacterial division and wide conservation across bacteria species, FtsZ is an appealing drug target. A growing number of small molecules have been reported to interact with FtsZ and to affect bacterial cell division. Among them a difluoro-benzamide derivative (PC190723) served to validate FtsZ as an antibacterial target as it was shown to effectively inhibits bacterial cell division, to have in vitro bactericidal activity against staphylococci, including methicillin- and MDR resistant Staphylococcus aureus and to protect mice from a lethal dose of S. aureus. Effective inhibition of FtsZ stops cell division, triggers cell enlargement and subsequent lysis, leading to bacteria death, indicating that FtsZ is a suitable target for antibiotic discover. One major challenge in antibiotic drug discovery is indeed to develop molecules able to rapidly penetrate the bacterial cell envelope to achieve a lethal intracellular drug accumulation. To enable nucleotide FtsZ inhibitors to cross the bacterial cell envelope, we propose to temporary block the free phosphonic functional group of the molecule, masking its acidic oxygen atoms with metabolically labile and non-toxic protecting groups to produce a charge-neutral compound (prodrug). Such prodrugs with increased lipophilicity, will cross the bacterial cell envelope and once inside upon activation will release the antimicrobial drug. As additional advantage these prodrugs having one or more phosphate groups attached to the nucleoside, do not require all the phosphorylation steps decreasing the chance for the bacteria to become resistance through mutation of the phosphorylating enzymes. Phosphate prodrug approaches have been successfully applied to antiviral and anticancer nucleoside analogues with many of these drugs reaching the clinic. It is extremely important to establish if such powerful technologies have the potential to lead to novel therapeutics to fight AMR. Objective 1 is the design and synthesis of nucleotide prodrugs masking only the last phosphate group while keeping the others partially charged to stabilize the anhydride bonds. The student will investigate prodrugs, whose intracellular cleavage is based on an entirely pH-driven chemical hydrolysis or enzymatic activation processes. They will also optimize the nucleoside scaffold using in silico studies to identify more potent inhibitors. Objective 2 is the prodrugs chemical and enzymatic stability and their activation study by bacterial enzymes using HPLC to determine the halflives and LCMS to identify metabolites. Objective 3 is the evaluation of the in vitro prodrugs antibacterial, antibiofilm activity in planktonic culture as well as biofilm of multiple isolates of multi drug resistant bacteria and toxicity in human cell lines. We will examine cell division using fluorescence microscopy in FtsZ green fluorescent protein labelled bacteria. Objective 4 is the study on the bacterial response to the novel prodrugs to establish if they can escape pre-existing resistance mechanisms. We will examine phenotypic responses to prodrugs, conducting real-time diffusion-mutation assays and microfluidic single-cell experiments.Academic criteria: Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.English requirements: If English is not your first language you will need to meet the English language requirements English language requirements for postgraduate students - Study - Cardiff UniversityHow to ApplyA list of all the projects and how to apply is available on the DTP’s website at GW4 BioMed MRC DTP - GW4 BioMed MRC DTPYou may apply for up to 2 projects and submit one application per candidate only.Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’. If successful, you will also need to make an application for an 'offer to study' to your chosen institution. Please complete the online application form linked from the DTP’s website by 5.00pm on Monday, 4th November 2024. If you are shortlisted for interview, you will be notified from Friday, 20th December 2024. Interviews will be held virtually on 23rd and 24th January 2025. Start date - 1st October 2025.SupervisorsDr Michaela Serpi - People - Cardiff UniversityDr Maisem Laabei - Our People (bristol.ac.uk)Tobias Bergmiller | Biosciences | University of ExeterProfessor Ian Fallis - People - Cardiff UniversityFor informal enquiries, please contact [email protected] For project related queries, please contact the respective supervisors listed on the project descriptions on the DTP’s website.