European Gram Negative Antibacterial Engine
Lead Research Organisation:
John Innes Centre
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The intensive use and misuse of antibiotics has resulted in antibiotic resistance in essentially all human bacterial pathogens. This is especially true when considering resistant Gram-negative infections where resistance is rising and use of drugs of last resort, such as colistin, is increasing. The New Drugs 4 Bad Bugs (ND4BB) initiative is a series of programmes designed to directly address some of the scientific challenges associated with antibacterial drug discovery and development. The ND4BB ENABLE consortium will meet these challenges by creating and optimising a portfolio of new antibiotics ranging from Hits through Phase 1 clinical studies.
The goals of the ENABLE consortium are to:
1. create a drug discovery platform with the expertise and resource base to prosecute multiple antibacterial programmes in parallel;
2. increase the overall pipeline in the antibacterial area by applying this platform to optimise a variety of antibacterial programmes.
More specifically the key objectives of the consortium are designed to increase the overall pipeline of high quality, novel mode of action medicines to treat serious systemic Gram-negative infections by identifying three antibacterial Leads, two antibacterial Candidates and progressing at least one compound into preclinical and Phase 1 clinical studies. The platform group is made up of academics and SMEs from across Europe with diverse expertise and includes 4 large pharma companies. The consortium will provide a unique opportunity for a productive collaboration between academic researchers and industry.
The role of the JIC group in this consortium is to evaluate compounds from other consortium partners as inhibitors of topoisomerases (DNA gyrase and topo IV) from various Gram-negative bacterial species. Positive compounds will be investigated further in terms of their mechanisms of inhibition and structures of the ligand-target complexes using X-ray crystallography.
The goals of the ENABLE consortium are to:
1. create a drug discovery platform with the expertise and resource base to prosecute multiple antibacterial programmes in parallel;
2. increase the overall pipeline in the antibacterial area by applying this platform to optimise a variety of antibacterial programmes.
More specifically the key objectives of the consortium are designed to increase the overall pipeline of high quality, novel mode of action medicines to treat serious systemic Gram-negative infections by identifying three antibacterial Leads, two antibacterial Candidates and progressing at least one compound into preclinical and Phase 1 clinical studies. The platform group is made up of academics and SMEs from across Europe with diverse expertise and includes 4 large pharma companies. The consortium will provide a unique opportunity for a productive collaboration between academic researchers and industry.
The role of the JIC group in this consortium is to evaluate compounds from other consortium partners as inhibitors of topoisomerases (DNA gyrase and topo IV) from various Gram-negative bacterial species. Positive compounds will be investigated further in terms of their mechanisms of inhibition and structures of the ligand-target complexes using X-ray crystallography.
Planned Impact
unavailable
Publications
Bax BD
(2019)
DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion.
in Journal of molecular biology
Chan PF
(2017)
Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.
in Proceedings of the National Academy of Sciences of the United States of America
Cotman AE
(2023)
Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa.
in Journal of medicinal chemistry
Durcik M
(2023)
New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus
in Journal of Medicinal Chemistry
Germe T
(2018)
A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.
in Nucleic acids research
Jeannot F
(2018)
Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones.
in Journal of medicinal chemistry
Sterle M
(2023)
Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.
in ACS omega
Zidar N
(2024)
Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.
in Bioorganic & medicinal chemistry
| Description | We have collaborated on the development of two new groups of antibiotics targeted to Gram-negative pathogenic bacteria; 4 papers published so far. |
| Exploitation Route | The companies involved in the consortium are in a position to develop the compounds into clinically useable antibiotics |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| URL | http://nd4bb-enable.eu/ |
| Description | Consortium compounds are using new findings for drug discovery. Although the first two groups of compounds have been dropped by the consortium, we are continuing to pursue one of these with collaborators in Leeds. Also we are now investigating another group of compounds with colleagues from Univ Ljubljana (Slovenia). |
| First Year Of Impact | 2020 |
| Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | Exploring novel binding pockets in DNA gyrase and DNA topoisomerase IV to address antibiotic resistance |
| Amount | £642,171 (GBP) |
| Funding ID | BB/V006983/ |
| Organisation | University of Leeds |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 06/2021 |
| End | 06/2024 |
| Description | Anders Karlen |
| Organisation | Uppsala University |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | We have assayed compounds synthesised by partner |
| Collaborator Contribution | They have synthesised compounds |
| Impact | Publications |
| Start Year | 2014 |
| Description | Bax |
| Organisation | Cardiff University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have performed mechanistic enzymology work to complement the structural biology performed by Bax and others. |
| Collaborator Contribution | They have established a crystallography platform to analyse structures of topoisomerase-DNA-drug complexes. That expertise has now been transferred to JIC. |
| Impact | 3 Research publications.: 1. B. D. Bax, G. Murshudov, A. Maxwell, T. Germe, DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion. J Mol Biol 431, 3427-3449 (2019). 2. P. F. Chan et al., Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proc Natl Acad Sci U S A 114, E4492-E4500 (2017). 3. T. Germe et al., A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Res 46, 4114-4128 (2018). Multi-disciplinary: biochemistry, crystallography, molecular biology |
| Start Year | 2014 |
| Description | Danijel Kikelj |
| Organisation | University of Ljubljana |
| Department | University Medical Centre Ljubljana |
| Country | Slovenia |
| Sector | Hospitals |
| PI Contribution | Assayed compounds synthesised by partner |
| Collaborator Contribution | Synthesised series of compounds for testing by us |
| Impact | Other publications |
| Start Year | 2019 |
| Description | Fishwick |
| Organisation | University of Leeds |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have been testing compounds synthesised by the med chem research team in Leeds |
| Collaborator Contribution | Using information provided by us, they have been using computational and medicinal chemistry methods to synthesise novel compounds that have antibacterial potential |
| Impact | Grant application to BBSRV funded 2 papers: 1. S. Narramore, C. E. M. Stevenson, A. Maxwell, D. M. Lawson, C. W. G. Fishwick, New insights into the binding mode of pyridine-3-carboxamide inhibitors of E. coli DNA gyrase. Bioorg Med Chem 27, 3546-3550 (2019). 2. K. M. Orritt, A. Maxwell, C. W. Fishwick, M. J. McPhillie, Exploitation of a novel allosteric binding region in DNA gyrase and its implications for antibacterial drug discovery. Future Medicinal Chemistry 13, 2125-2127 (2021). Multidisciplnary: biochemistry, structural biology, medicinal chemistry, computational chemistry |
| Start Year | 2017 |
| Description | IMI consortium: ENABLE |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | We carried out the biochemical/molecular biological aspects of the projects |
| Collaborator Contribution | Drug discovery and medicinal chemistry and x-ray crystallography |
| Impact | 4 papers: 1. B. D. Bax, G. Murshudov, A. Maxwell, T. Germe, DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion. J Mol Biol 431, 3427-3449 (2019). 2. P. F. Chan et al., Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proc Natl Acad Sci U S A 114, E4492-E4500 (2017). 3. T. Germe et al., A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Res 46, 4114-4128 (2018). 4. F. Jeannot et al., Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones. J Med Chem 61, 3565-3581 (2018). Multidisciplinary |
| Start Year | 2014 |