Projects

We are currently advertising DTP and CASE studentships for October 2019 start. The deadline for applications is the 26th November 2018.

27 / 09 / 2018

The mechanism of the bacterial toxin Microcin B17: the application of Cryo-EM (MAXWELL_J19DTP)

how to apply

Antimicrobial resistance (AMR) is a major threat to mankind.  DNA gyrase is a bacterial type II topoisomerase, and a well-validated target for antibacterials, including the highly-successful fluoroquinolone antibiotics (FQs); but resistance to these drugs is a serious problem.  We are investigating potential replacements for FQs.  Microcin B17 (MccB17) is a ~3-kDa post-translationally modified peptide produced by Escherichia coli strains harbouring the MccB17 plasmid.  MccB17 kills other bacteria by targeting gyrase via a mechanism related to that of FQs: it stabilises the covalent gyrase-DNA cleavage complex, which leads to double-stranded chromosomal breaks and cell death.  However, its mode of action is different from that of FQs making it an attractive prospect for developing novel gyrase-targeted antibiotics.  We would like to explore the development of other compounds targeting the MccB17-binding site, but this is currently not possible without knowledge of the gyrase-MccB17 complex structure.

The aims of this project are to achieve a molecular understanding of the mode of action of microcin B17 on DNA gyrase and to harness this knowledge for the development of new antibacterial agents.  We propose a variety of structural and molecular biology approaches to tackle this problem that will give the student a broad experience of research methods.  These will include: mutagenesis, cloning, biochemical and biophysical assays, and structural biology methods (X-ray crystallography and Cryo-EM).