Identification of novel inhibitory compounds targeting the master bacterial DNA replication initiation protein DnaA
Lead Research Organisation:
Newcastle University
Department Name: Inst for Cell and Molecular Biosciences
Abstract
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People |
ORCID iD |
| Heath Murray (Principal Investigator) |
| Description | In order to identify new antibiotics to combat the growing threat posed by multi-drug resistant bacteria, we have previously developed a high throughput in vivo growth assay to detect inhibitors of the master bacterial DNA replication initiation protein DnaA. Following a primary screen, the next key step would be to distinguish molecules acting directly upon DnaA. This aim will require an analysis of DnaA function in vitro using purified components. To achieve this goal we have recently created a novel in vitro assay to probe the ability of DnaA to perform all of its activities required for DNA duplex unwinding. |
| Exploitation Route | This assay we have developed could be used to identify factors, either small molecules of proteins, that regulate DNA duplex unwinding by DnaA. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Description | A screen to identify novel antibiotics targeting the master bacterial DNA replication initiation protein DnaA |
| Organisation | European Commission |
| Department | Innovative Medicines Initiative (IMI) |
| Country | Belgium |
| Sector | Public |
| PI Contribution | Antibiotics with novel modes of action are required to combat the growing threat posed by multidrug resistant bacteria (MRSA, Mycobacterium tuberculosis). No antibiotics act directly on the bacterial DNA replication machinery; DNA synthesis is thus an underexploited drug target. DnaA is the master bacterial DNA replication initiator protein. DnaA is essential, highly conserved, and distinct from eukaryotic initiator proteins. These properties make DnaA an attractive drug target and compounds capable of inhibiting DnaA activity will constitute a new group of antibiotics. The Murray Lab has developed a cell-based high-throughput screening assay for the discovery of compounds that specifically target DnaA. |
| Collaborator Contribution | The European Lead Factory has performed high-throughput screening on >350,000 and identified >300 compounds that satisfy the screening assay. |
| Impact | The screening program is on-going. |
| Start Year | 2015 |