The Structural Basis For Heme Piracy

Heme is an essential nutrient for the bacterial pathogen Haemophilus influenzae, which causes serious respiratory infections, otitis media and meningitis. During infection, these bacteria obtain heme from the host protein hemoglobin. To achieve this H. influenzae produces outer-membrane transporters that bind hemoglobin and extract its heme cofactor. Heme piracy performed by these transporters is often essential for virulence, and so they represent promising targets for antimicrobial intervention. This exciting project aims to determine the structural and biochemical basis of H. influenzae iron piracy from hemoglobin, It will then apply this knowledge to develop inhibitors that block the outer-membrane transporters targeting these host proteins, preventing the bacteria from obtaining these nutrients and causing infection. The project will apply cutting-edge structural techniques (including cryo-EM and X-ray crystallography) to determine the structures of these transporters in complex with hemoglobin. These structures will be validated using multifaceted biochemical techniques and cellular microbiological analysis. This information will be exploited to design inhibitors using structure-guided inhibitor design and directed library screening approaches.