Antibiotic discovery in Streptomyces bacteria (HUTCHINGS_J27DTP)

Antimicrobial resistance in disease-causing bacteria represents a significant threat to global health. To address this, we urgently need to replenish the antibiotic discovery pipeline with new molecules. Most antibiotics in clinical use are derived from specialised metabolites made by Streptomyces bacteria that were discovered last century. However, genome analysis indicates that we have discovered only 3% of the specialised metabolites encoded by these bacteria with the rest remaining “silent” under laboratory growth conditions. To activate these silent pathways, we first need to understand how they are controlled.

Streptomyces bacteria have complex lifecycles, and antibiotic production is typically coordinated with sporulation. We have discovered a key regulator which controls the spore phase of the lifecycle and, when it is overexpressed, it activates numerous silent pathways in the model organism Streptomyces venezuelae. We propose that this regulator blocks the expression of genes required for sporulation and activates genes required for spore germination. We hypothesise that it activates numerous “silent” specialised metabolite biosynthetic pathways that are required to protect germinating spores against predation. We further propose that over-expressing this regulator in diverse Streptomyces species will switch on the production of numerous silent pathways and lead to the discovery of lots of new antibiotics.
In this project the student will test these hypotheses by identifying all the gene targets of this regulator in S. venezuelae and examining the effects of its overexpression on specialised metabolism in environmental Streptomyces strains. This will include the use of comparative metabolomics to identify new antibiotics.