Dr Natalie Tatum (pictured right) of the Cancer Research UK, Drug Discovery Centre, Newcastle University, wrote the winning application for her work on antimicrobial resistance, describing support from CoSeC in the form of CCP4 study weekends, feedback received when presenting, and the intensive training received at the 2019, CCP5 summer school. Dr Tatum's work in the field of antimicrobial resistance focuses on the bacterium responsible for tuberculosis (i.e. Mycobacterium tuberculosis) a multidrug- and extensively- resistant infection complicating the treatment of HIV and malaria, two diseases endemic in sub-Saharan Africa.
The antibiotic isoniazid is used in active and latent infections but resistance is prevalent. Ethionamide is an isoniazid analogue used as a pro-drug, but its activation is inhibited by EthR –a mycobacterium tuberculosis gene. Inhibiting EthR in the presence of ethionamide enables better tolerance and activity of the antibiotic, effectively killing the bacteria.
Natalie’s crystallographic training, supported by CCP4 Study Weekends and feedback received when presenting at the CCP4 Northern Meetings, informed her approach to both structure analysis and, later, co-crystallisation and determination of her own EthR-inhibitor complexes. To confirm crystallographic findings of a single EthR posed complex at the binding site, Natalie explored binding energy simulations using molecular dynamics and attended the 2019 CCP5 Summer School where, alongside intensive training in molecular simulations, she was given the opportunity to present her work.J. Phys. Chem. Lett. 2019, 10, 9, 2244-2249
By combining computational and crystallographic techniques, Natalie developed methods to identify and assess quantitatively and qualitatively novel inhibitors of EthR that show ethionamide-boosting capability in biological assay. During her PhD, she developed a virtual screening approach, that used the known crystal structures of EthR-inhibitor complexes to train and test protocols, and filter a database of potential molecules based on the structure and properties of the binding site.
As yet, no EthR inhibitor has entered pre-clinical or clinical trials, and those closest are of a single chemo-type. By exploring multiple chemo-types and presenting active compounds, Natalie’s research provides novel leads for ethionamide-boosting to treat tuberculosis infections. This work continues with collaborators (listed below) seeking to build on these new chemo-types, providing a range of options for pre-clinical development, thereby maximising the chances of success through the drug development pipeline.
The Coronavirus pandemic has caused a delay in presenting Natalie with the full extent of her well-deserved prizes until later in the year. In the meantime, on behalf of CoSeC we say Congratulations Natalie, and we wish you every success in your promising career!
Key Collaborators:
Dr. Ehmke Pohl, Durham University (PhD Supervisor)
Prof. Lynn Kamerlin, Uppsala University (EMBO Short Term Fellowship Supervisor)
Dr. Fernanda Duarte, Oxford University (post-doc in Uppsala at time of EMBO Short Term Fellowship)
Professor Nicolas Willand "who published the first EthR inhibitors in 2009 and has been supportive of our parallel work; his group performed some biological validation experiments of our screening output for our 2017 paper."
Key publications associated with this work:
Evidence known about EthR inhibitors adopting two conformations in docking (Tatum et al, 2013)
Publication of our virtual screening protocol, co-crystal complexes and biological validation (Tatum et al, 2017)
Our computational study which shows relative binding energies and per-residue contributions to binding can aid accurate pose selection (Tatum et al 2019)
