Our laboratory is interested in the molecular mechanisms that underlie the adaptive responses of bacteria to stress. We are particularly interested in stress responses in the actinobacteria, including the antibiotic-producing Streptomyces sp. and the major human pathogen Mycobacterium tuberculosis.

Current projects

RNA polymerase structure and function

In bacteria control of gene expression occurs primarily at the level of transcription initiation. We are studying novel aspects of actinomycete RNA polymerase including the role of a small RNA polymerase binding protein that activates transcription. One research aim is to facilitate the development of new antibiotics that inhibit RNA polymerase, a proven target in the fight against tuberculosis.

Redox sensing

The Rex protein is a sensor of NADH/NAD+ redox poise, and is widespread in Gram positive bacteria. In response to an increase in NADH/NAD+ ratio caused, for example, by hypoxia, Rex dissociates from its operator sites, thereby inducing the expression of genes that help restore the redox balance (e.g. NADH dehydrogenase). The SigR-RsrA (SigH-RshA in M. tuberculosis) senses and responds to an oxidative shift in the cytoplasmic thiol-disulphide ratio. The key sensor of the system is RsrA, which forms an intramolecular disulphide bond in response to the stress, which induces a structural change that leads to the release of the sigma factor SigR. In S. coelicolor SigR controls a large regulon including genes that restore thiol-disulphide redox balance or degrade aggregated proteins.  

The Paget Lab Website