Project title: Designing peptide and small molecule inhibitors for the treatment of Gram-negative bacterial infections.
Summary: The rise of antibiotic resistance is an urgent and growing problem in contemporary medicine. It has emerged as one of the pre-eminent public health concerns of the 21st century. An example is the opportunistic pathogen Pseudomonas aeruginosa. It is a major cause of healthcare-associated infections and is increasingly resistant to many antibiotics. One infection method widely used by Pseudomonas (and many others) involves a protein nanomachine called the Type Three Secretion System (T3SS). In T3SS infection bacteria synthesise toxin proteins and transport them through a channel made of proteins that directly links the insides of the bacteria and host cell. Here the “toxins” modulate host cell signal cascades, which can lead to apoptosis, and thus enable bacterial survival/proliferation. The formation and assembly of the protein channel is critical to infection. Importantly, needle and pore formation and thus infection can only occur when these forming proteins are bound by specific chaperones in the bacterial cytosol. The protein/chaperone complexes can then traffic across the bacterial cell membranes, dissociate and then form the needle or the pore. The significance of the protein/chaperone complex to bacterial pathogenicity is easily highlighted by studies that show chaperone null bacterial strains are non-invasive to eukaryotic cells. This PhD project seeks to develop and biochemically/biophysically characterise molecules that can bind to T3SS translocator chaperones and disrupt their interactions with their cargo - thus inhibiting the movement of toxins from the bacteria to the host cell. Our long-term aims are to develop these molecules into drug candidates.