Engineering Streptomyces bacteria to over produce antibiotics

HUTCHINGS_J22DTP1

Most antibiotics in clinical use are made by a group of soil bacteria called Streptomyces and were discovered between 1940 and 1960. Their misuse over the last 60 years has led to widespread resistance in disease causing bacteria and some life-threatening infections can no longer be treated with antibiotics. The O’Neil report on AntiMicrobial Resistance predicts that it will be the major cause of death (10M a year, worldwide) by 2050 and recommends stimulating early stage antibiotic discovery.

This project is focussed on understanding conserved stress signalling pathways that control antibiotic production in Streptomyces species. These bacteria only make ~10% of the antibiotics they encode under laboratory conditions and the rest are ‘silent’ which means they are made in nature but not when we grow them in the lab. If we can understand and manipulate the signalling pathways that control their production we can discover new antibiotics to tackle drug resistant infections. We know these bacteria make antibiotics in response to external threats and stresses and we have discovered two interlinked signal transduction pathways which sense stresses to the cell envelope (an essential structure that surrounds and protects the cell) and switches on the production of antibiotics. Deletion of one pathway increases production of the second pathway and leads to over production of antibiotics. In this project you will determine how and why this happens and manipulate these pathways to induce the production of new and useful antibiotics.

You will be based at the John Innes Centre, a world leading centre of excellence in microbiology and be co-supervised by Profs Matt Hutchings (a microbiologist) and Barrie Wilkinson (a natural products chemist) and at UEA by Prof Nick Le Brun (a biochemist). You will receive excellent, interdisciplinary training and use cutting edge biochemical and genetic techniques.

References

Devine R, McDonald H, Qin Z, Arnold C, Noble K, Chandra G, Wilkinson B, Hutchings MI (2021). Rewiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising new antibacterial compounds. Cell Chem Biol. 28:1-9.

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

Qin Z, Munnoch, JT, Devine R, Holmes N, Seipke RF, Wilkinson B, Hutchings MI (2017). Formicamycins, antibacterial polyketides produced by Streptomyces formicae isolated from African Tetraponera plant-ants. Chem Sci. 8:3218-27.