Developing new tools for antibiotic discovery in Streptomyces bacteria (HUTCHINGS_U17DTP)

Almost all of the antibiotics in clinical use are derived from the natural products (NPs) of Streptomyces bacteria, which are widespread in soil. NP discovery peaked in the mid 1950s but new advances in DNA sequencing combined with the alarming rise in Antimicrobial Resistance (AMR) has led to renewed interest in these bacteria and their antibiotics in the 21st century. We know from genome sequencing that the vast majority of Streptomyces NPs are not made under laboratory conditions and our work is focused on developing tools to switch on these silent pathways and facilitate the discovery of new antimicrobials. We have assembled a collection of more than 400 Streptomyces strains and we estimate that more than 80% of their NP biosynthesis pathways are silent under laboratory conditions.

In this project the successful candidate will analyse an essential and conserved regulator that we discovered in Streptomyces. This regulator appears to coordinate cell division and antibiotic production in these bacteria. It binds to the promoters of essential DNA replication and cell division genes and to 24 of the 32 NP biosynthetic gene clusters in the model organism S. venezuelae. Remarkably it also interacts directly with proteins involved in DNA replication and antibiotic production. Artificially activating the regulator through a gain of function mutation switches on numerous silent NPs in S. venezuelae, including antibiotics. You will examine the role of this protein in regulating DNA replication, cell division and antibiotic production in S. venezuelae and also express gain of function proteins in novel genome sequenced Streptomyces species from our collection to see if this protein can be used as a general tool to activate production of silent and novel antibiotics.