Multi-level regulation of antibiotic production by the conserved response regulator MtrA

HUTCHINGS_J21DTP2

Most antibiotics in clinical use are made by soil bacteria in the genus Streptomyces and were discovered between 1940 and 1960. Misuse of antibiotics over the last 60 years has led to widespread resistance and some life-threatening infections can no longer be treated. 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 and exploiting a conserved signalling pathway which controls antibiotic production in Streptomyces species. They only make ~10% of their antibiotics under lab conditions and the rest are ‘cryptic’ which means they are made in nature but not in the lab. If we can understand and manipulate the signalling pathways that control their production we can discover many new antibiotics. Antibiotic production is linked to sporulation and we have identified a master regulator called MtrA which coordinates these processes. MtrA represses antibiotic production and deletion of the mtrA gene activates the production of cryptic antibiotics in all the Streptomyces species we have tested. In this project you will analyse the cellular role of MtrA and identify a cryptic antibiotic switched on in an S. venezuelae mtrA mutant.

You will be based at the John Innes Centre, a world leading centre of excellence in microbiology and you will receive excellent, interdisciplinary training and use cutting edge biochemical and genetic techniques to characterise the function of MtrA and identify new antibiotics in Streptomyces bacteria.

References:

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

Qin Z, Devine R, Hutchings MI and Wilkinson B (2019). A role for ABM domain proteins in fidelity control during aromatic polyketide biosynthesis. Nature Comms 10:3611

Som NF, Heine D, Holmes N, Munnoch JT, Chandra G, Seipke RF, Hoskisson PA, Wilkinson B and Hutchings MI (2017). The conserved actinobacterial two-component system MtrAB coordinates chloramphenicol production with sporulation in Streptomyces venezuelae NRRL B-65442. Frontiers Microbiol. 8:1145.