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Mabell Orobio Mosquera

Mabell

PhD Student

Email: m.r.orobiomosquera@qmul.ac.uk

Profile

Project Title: Design of bicyclic peptide molecules inhibitors of the T3SS chaperone-translocator complexes present in Pseudomonas aeruginosa

Summary: The rise of antibiotic resistance is an urgent and growing problem in contemporary medicine. One infection method widely used by many gram-negative bacteria involves a protein nanomachine called the Type Three Secretion System (T3SS). In T3SS infection bacteria synthesize toxin proteins and transport them through a channel made of proteins that directly link 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 are critical to infection. The channel complex comprises over 20 proteins that combine to form a base in the bacteria, a hollow needle (projects from the bacteria to the host cell) and a pore into the host cell. The needle is composed of one fibre-forming protein, whereas the pore is mainly composed of two large transmembrane domains containing proteins (translocators). The chaperon protein is responsible for maintaining the translocator in the secretion mode stage and facilitating its transport through the T3SS needle.

The study focuses on developing libraries of bicycle peptide molecules with moderate sizes, high selectivity, and high binding affinities to target specific motifs of the T3SS components responsible for the translocator formation and disrupt their interactions.  Also, biochemically/biophysically characterizing the important binding interfaces of the chaperon-translocator concave interface. Thus, inhibiting either T3SS function and/or the movement of toxins from the bacteria to the host cell.

The long-term aims are to develop these molecules into drug candidates, implementing molecular biology, ribosome display, recombinant protein production and biochemical/biophysical assays (e.g. C.D. spectroscopy, ITC and NMR)

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