Antibiotic discovery in Streptomyces bacteria

The continued evolution of antimicrobial resistance (AMR) in pathogenic bacteria represents a significant threat to global health and new antibiotics with novel mechanisms of action are urgently needed. Most antibiotics currently used in the clinic are derived from the specialised metabolites of Streptomyces bacterial strains isolated >60 years ago. On average, a single Streptomyces strain encodes between 20 and 60 specialised metabolite biosynthetic gene clusters (BGCs), many of which will produce compounds with clinically relevant bioactivity. However, only 3% of these BGCs have been matched to molecules, meaning many new compounds remain to be discovered. To access the full biosynthetic potential of Streptomyces species, cryptic pathways encoding new molecules need to be switched on under laboratory conditions, so we urgently need to understand how the expression of these BGCs is controlled.

The aim of this project is to understand how the production of antibiotics is coordinated with sporulation, the stationary phase of the Streptomyces life cycle. We have discovered that a regulator called WblA is involved in regulating growth and differentiation and antibiotic production. Deletion of the wblA gene results in the over production of antibiotics and we hypothesise that WblA directly controls antibiotic biosynthetic pathways by interacting and regulating target gene promoters but also by interacting with other proteins.
In this project you will test this hypothesis by examining the interactions of WblA with genes and proteins to precisely define how it controls antibiotic production. You will also use comparative metabolomics between wild-type and ∆wblA mutant strains to see which new molecules are produced when WblA is lost from the cell.

References

Hutchings MI, Truman A and Wilkinson B (2019). Antibiotics: past, present and future. Curr Op Microbiol. 51:72-80.

Devine R, McDonald H, Qin X, Arnold C, Noble K, Chandra G, Wilkinson B and Hutchings MI (2021). Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds. Cell Chem Biol. 28:515-23.

Gray E, Stewart MYY, Hanwell L, Crack JC, Devine R, Stevenson C, Volbeda A, Johnston AWB, Fontilla-Camps JC, Hutchings MI, Todd JD and Le Brun NE (2023). Stabilisation of the RirA [4Fe-4S] cluster results in loss of iron-sensing function. Chem Sci. 14:9744

MacLean TC, Beaton A, Martins C, Saalbach G, Chandra G, Wilkinson B* and Hutchings MI* (2023). Evidence of a role for CutRS and actinorhodin in the secretion stress response in Streptomyces coelicolor M145. Microbiology 169:001358

Feeney MA, Newitt, JT…..Duncan, KR, Hutchings MI (2022). ActinoBase: tools and protocols for researchers working on Streptomyces and other filamentous actinobacteria. Microbial Genomics. 8:000824.