Towards the development of a novel class of broad-spectrum anti-infective drugs

About the Project

Through exceptionally strong research collaborations at the interface of chemistry, biology, and medicine, we have applied innovative thinking to the field of (Minor Groove Binders) MGBs to develop a novel platform for drug discovery with the potential to treat an impressive range of diseases, including bacterial, fungal, parasitic, and viral infections. This platform, the Strathclyde Minor Groove Binders (S-MGBs) has evolved from the first discovered MGB, distamycin, and we can design novel compounds with tailored activities through a detailed understanding of DNA binding, sequence selectivity, and physicochemical characteristics. MGB lead compounds have in vivo activity (MIC = 0.2 µg/mL) against Gram-positive bacteria. In December 2015 our commercial partner, MGB Biopharma, completed the successful Phase I Clinical Trial (NCT02518607) of our lead candidate MGB-BP-3 for the treatment of Clostridium difficile infections; it is now going through Phase IIa.

MGB-BP-3 is taken up selectively by bacterial cells and interacts with bacterial DNA. Its mode of action is consistent with the arrest of transcription of a number of essential genes. Thus, the multi-target nature of binding of MGB-BP-3 may indicate why we have never seen mutation to resistance for this compound. Several bacterial resistance mechanisms would thus have to be developed at once for a new MGB drug to become ineffective. This indicates that MGBs are very suitable drugs for the AMR era because several new bacterial resistance mechanisms would thus have to evolve together for a new MGB drug to become ineffective.

Recently, researchers at the University of Strathclyde, including the Scott research group, have begun to significantly expand the therapeutic potential of the S-MGB drug discovery platform. Specifically, efforts have resulted in the selection of lead compounds for the treatment of: Animal African Trypanosomiasis with the University of Glasgow, the University of Edinburgh and GALVmed;1 Human African Trypanosomiasis and Malaria with Griffith University;2 Tuberculosis with University of Cape Town;3 Cryptococus neoformas and Candida auris with University of Manchester;4 and a variety of cancers with the University of Huddersfield and Strathclyde.5

There remains much work that can be done in developing new generations of S-MGBs with improved activities, reduced toxicity, and organism specificity, in order to progress compounds to pre-clinical development and beyond.

Interested potential PhD candidates will have the opportunity to engage in our drug design programme, but will be able to choose the specific focus of the project that most interests them, in discussion with the PI. For example, whilst any project will include a significant organic and medicinal chemistry component, there will be the potential to gain skills in biochemical assays (such as enzyme inhibition), biophysical studies (such as UV-vis and NMR) and also biology (in vitro cell assays either in the PI’s lab or with collaborators). Moreover, the target infectious organism is also up for discussion.

Training Environment

Using advanced hit compounds identified from preliminary studies, in collaboration with national and international partners, the prospective student will carry out a comprehensive and systematic drug discovery campaign to identify new lead compounds for invasive fungal infections. This will involve routine and complex synthesis techniques, compound characterization using NMR, Mass Spec etc., and also target engagement studies using biophysical techniques. There may also be the opportunity to carryout in vitro biological evaluation of these compounds against fungal spp. in the labs of our various collaborators.

This project will suit a student with a background in synthetic organic chemistry or medicinal chemistry. Although it could be tailored to those wishing to pursue a biologically-focused project.

In addition to undertaking cutting edge research, students are also registered for the Postgraduate Certificate in Researcher Development (PGCert), which is a supplementary qualification that develops a student’s skills, networks and career prospects.

How To Apply

An upper second-class UK Honours degree or overseas equivalent in a relevant discipline is required. If English is not your first language, you must have an IELTS score of at least 6.5 with no component below 5.5

Interested candidates should email Dr Fraser Scott in the first instance.

Funding Notes

This project is suitable for self-funded candidates only. This may be through a personal scholarship that has already been secured or for an identified scholarship that a candidate would like to apply for with the supervisor.

References

1. F. Giordani, F. J. Scott et al., J. Med. Chem., 2019, 62, 3021-3035.
2. F. J. Scott et al., Euro. J. Med. Chem., 2016, 116, 116–125.
3. H. Lerato, F. J. Scott et al. J. Antimicrob Chemother., 2017, 72, 3334–3341.
4. F. J. Scott et al., Eur J Med Chem., 2017, 18, 561-572.
5. F. J. Scott et al., Bioorg. Med. Chem. Lett., 2016, 26, 3478-86