Targeting iron piracy from host proteins by Neisseria and Haemophilus spp. for the development of novel antimicrobials

Bacteria of the genera Neisseria and Haemophilus are significant human pathogens, causing both localised and systemic infection. These infections are of major importance due their severity and prevalence. As a result of incomplete vaccine coverage and the emergence of antibiotic resistance, new strategies for their treatment and prevention are urgently required. One possible strategy for combating these pathogens is to prevent these bacteria from obtaining the essential nutrient iron during infection. Disease causing Neisseria and Haemophilus spp. have specialised to the human host and as such they rely on the host iron-containing proteins transferrin, lactoferrin and hemoglobin as their major source of iron. These bacteria obtain iron from these proteins through specialised cell surface transporters, which bind the target protein and liberate its iron, before transporting it into the bacterial cell. A number of studies have shown these transporters to be important virulence factors in animal models and infection of humans. In the proposed research I will use my extensive skills in the structural and biochemical characterisation of membrane proteins, to determine the molecular details of how these transporters engage in iron piracy, by binding their substrate and liberating its iron payload. I will apply my experience in molecular and cellular microbiology to determine how these transporters function in vivo, using a specially engineered bacterial strain. I will utilise an exciting new method to generate protein nanobodies that bind these transporters and block substrate binding and iron uptake. In order target iron transporters to prevent infection a detailed understanding of how they function is essential. This research will provide this detail and develop tools that will pave the way for the exploitation of these transporters as antivirulence targets.