Postgraduate research opportunities

Disarm and disengage: repurposing old drugs for bad bugs

Microbiology and Industrial Biotechnology; Streptomyces; Antimicrobial resistance; natural product biosynthesis

Number of places

1

Opens

14 February 2020

Deadline

31 July 2020

Duration

36 Months

Eligibility

BSc (hons) 2.i or First Class in Microbiology, Biochemistry or Molecular Biology

Project Details

By 2050 deaths attributable to AMR are likely to reach 10 million, surpassing those of cancer and diabetes14. In the UK, recent data confirm this trend, with widespread resistance particularly prevalent amongst Gram-negative organisms that are common causes of bacteremias. The human burden of the six most common drug-resistant bacteria alone is >33,000 deaths annually with an economic burden of ~€1.5 Billion per year. Thus, to help ameliorate this human and economic burden, there is an urgent need for new strategies and novel therapeutics to control and treat infectious diseases with modes of action distinct from conventional antibiotics.

Natural products have been the primary source of clinical antibiotics in addition to anticancer, immunosuppressant, and other therapeutically relevant molecules. The major producers of these molecules are the Actinobacteria, especially the soil-inhabiting genus Streptomyces. One such Streptomyces natural product is aurodox, in the Elfamycin class of molecules due to it targeting the prokaryotic elongation factor-Tu. Previously, the only known mode of action for aurodox was via EF‐Tu on the ribosome which blocks protein synthesis. Recently we demonstrated a second mode of action for aurodox in Gram-negative pathogens which prevents T3SS synthesis, blocking attachment and colonisation of host cells.

Our recent, unpublished work, has also identified and cloned the biosynthetic gene cluster and predicted the biosynthetic route that is responsible for the production of aurodox, thus enabling us to dissect the biosynthesis of aurodox and to potentially produce novel activities through genetic manipulation of the cluster. This project is focussed on dissecting the biosynthetic pathway with a view to using synthetic biology approaches to create novel derivatives of aurodox.

 

Techniques used:

 

Molecular biology, biochemistry, microbiology

Funding Details

Applicant will need to self-fund, find sponsorship for tuition and bench fees of £12,000 per annum for duration of studies

Supervisor

Primary Supervisor: Prof Paul A Hoskisson

Email: paul.hoskisson@strath.ac.uk

 

Secondary Supervisor: Dr Arnauld Javelle

Email: arnaud.javelle@strath.ac.uk

Further information

Chevrette, M.G., Gutiérrez-García, K., Selem-Mojica, N., Aguilar-Martínez, C., Yañez-Olvera, A., Ramos-Aboites, H. E., Hoskisson, P. A., & Barona-Gómez, F. (2020). Evolutionary dynamics of natural product biosynthesis in bacteria. Natural Product Reports (in Press).

 

Wollein Waldetoft, K., Gurney, J., Lachance, J., Hoskisson, P. A., & Brown, S. P. (2019). Evolving antibiotics against resistance A potential platform for natural product development? mBio 10, e02946-19.

 

Chevrette, M. G., Hoskisson, P. A., & Barona-Gómez, F. (2019) Enzyme Evolution in Secondary Metabolism. Comprehensive Natural Products III: Chemistry and Biology. Eds:  Byrne, C., Sajana, P. K., & Boobalan, R.

 

McKean, I., Sadler, J. C., Humphreys, L. D., Hoskisson, P. A., & Burley, G. (2019). S-Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C-Alkylation. Angewandte Chemie International Edition 58, 17583-17588.

 

McHugh, R., O'Boyle, N., Connolly, J., Hoskisson, P. A., & Roe, A. (2019) Characterisation of the mode of action of Aurodox, a Type III Secretion System inhibitor from Streptomyces goldiniensis. Infection and Immunity  87, e00595-18.

 

Hoskisson, P. A. & Fernández-Martínez, L.T (2018). Regulation of specialised metabolites in Actinobacteria -  Expanding the paradigms. Environmental Microbiology Reports 10, 231-238.

 

Schniete, J. K., Cruz-Morales, P., Selem, N., Fernández-Martínez, L.T., Hunter, I. S., Barona-Gómez, F., & Hoskisson, P. A. (2018). Expanding primary metabolism helps generate the metabolic robustness to facilitate antibiotic biosynthesis in Streptomyces. mBio 9, e02283-17.

Contact us

Primary Supervisor: Prof Paul A Hoskisson

Email: paul.hoskisson@strath.ac.uk