Antibiotic discovery in Streptomyces bacteria

The continued evolution of antimicrobial resistance (AMR) presents 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 strains isolated >60-years ago. On average, a single Streptomyces strain encodes between 25 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 bene 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 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 an essential regulator called WblE is likely essential because it activates the expression of dnaA which is required for DNA replication and cell division. However, WblE also interacts with another regulator called MtrA which is a master regulator of antibiotic production in Streptomyces species.

We hypothesise that MtrA and WblE work together to coordinate antibiotic production and sporulation and that manipulating the activity of these proteins can help us switch on the production of new antibiotics.

In this project you will test this hypothesis by examining the interactions of these proteins in more detail, and determining how essential genes like dnaA, which encodes the initiator protein for DNA replication, are controlled by MtrA and WblE You will also manipulate the levels of each regulator during the life cycle to try and activate the production of new antibiotics.