Tackling antibiotic resistance through blocking of signalling pathways

Antibiotic resistance is one of the grand challenges faced by modern medicine, and tremendous efforts are invested in
developing new treatments to slow its spread. One exciting approach is the development of anti-resistance drugs that do
not themselves inhibit bacteria, but instead block resistance and reinstate the usefulness of our existing antibiotics.
Many resistance mechanisms are tightly regulated by the bacteria and only expressed in the presence of antibiotics.
Dedicated signalling pathways detect the presence of drugs and transmit this information to the cell's interior to activate
gene expression. If signalling can be blocked, resistance can no longer be activated and the bacterium once again becomes
susceptible to the antibiotic.
In this PhD project, you will investigate the development and characterisation of peptide-based inhibitors of such a
signalling pathway. As a member of the Gebhard lab, you will tap into over 10 years' experience in signalling pathways
that control antibiotic resistance in Gram-positive bacteria. Specifically, you will focus on histidine kinases of the BceS
type. These proteins possess a coiled-coil structure at their core, which is known to be essential for their function. In an
exciting interdisciplinary collaboration, you will work with the Mason lab, who have pioneered the use of peptide
antagonists to disrupt coiled-coil protein function. This has had great success in the context of cancer and
neurodegenerative disease, and is now ready to be applied to bacterial signalling.
You will begin with in silico analyses of protein and peptide sequences, to define the most promising starting point for
inhibitor design. A combination of random and directed peptide screening approaches will identify functional antagonists,
which you will take forward for biochemical characterisation. This will be supported by the Porter lab in Exeter, who are
experts in bacterial kinase biochemistry. Antibiotic susceptibility and signalling assays will test the ability of your peptide
antagonists to block resistance in living cells. Finally, by comparing endogenously produced to externally added peptides,
you will begin to explore aspects of drug delivery, such as permeability to reach intracellular targets.