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Molecular basis of zinc acquisition by Streptococcus pneumoniae

Project Member(s): Deplazes, E.

Funding or Partner Organisation: National Health & Medical Research Council (NHMRC - Ideas Grants)
National Health & Medical Research Council (NHMRC - Ideas Grants)

Start year: 2020

Summary: Bacterial infection involves a constant tug-of-war between host and pathogen for nutrients essential to their survival. These include trace metals, such as zinc, that are critical for the viability of all pathogens. Part of the innate immune response of the host involves sequestration of essential trace metals in an attempt to starve invading pathogens and prevent their dissemination and propagation. Direct interference with the metal uptake pathways of bacterial pathogens attenuates their virulence and hence, is an exceptionally promising route for antimicrobial targeting. Zinc is an essential metal that is required for the growth and virulence of the major bacterial pathogen Streptococcus pneumoniae. S. pneumoniae acquires zinc from the host environment exclusively via the Adc permease, which the CI team has shown to be an essential virulence determinant and a viable drug target. Exciting preliminary work by the CI team has delivered major advances in understanding the mechanism by which this uptake pathway recruits zinc from the environment and facilitates transport into the cell. We have also made significant progress towards determining the three-dimensional structure of the AdcCB transporter. In this Project, we will combine a range of state-of-the-art methods including single molecule FRET, electron paramagnetic resonance spectroscopy, molecular dynamics and reconstituted proteoliposome transport assays to characterise the molecular basis of zinc recognition and show how selective zinc transport is achieved. We will also build on our major structural advances to solve the high-resolution structure of the AdcCB transporter. The outcomes of this work will be: (i) revealing how bacterial transporters achieve selective zinc uptake; and (ii) determining the high-resolution structure of a crucial bacterial virulence determinant. Translation of this work will leverage this knowledge in the development of antimicrobials targeting metal uptake pathways.

FOR Codes: Bacteriology , Characterisation of biological macromolecules, Proteins and peptides, Expanding Knowledge in the Biological Sciences, Bacteriology