From Structural and functional studies of essential and novel lipopolysaccharide transport and assembly membrane proteins to novel drug discoveries combating emerging multi-drug resistant pathogenic bacteria . (360G-Wellcome-106121_Z_14_Z)

£1,703,167

Multi-drug resistant bacterial infection is a huge globe health problem, and my research seeks to understand the detailed mechanisms of lipopolysaccharide transport membrane protein LptD/E and LptBCFG complexes, and use the knowledge gained from the studies for probe and drug discovery for combating multi-drug resistant bacteria. The membrane protein complexes LptD/E and LptBCFG are attractive drug targets, which has been demonstrated by Polyphor's compound POL7080, which targets LptD and kills Pseudomonas aeruginosa. Our research on the structure and function of LptD/E reduced form structure and LptC provide the promised evidence that the LPS transport can be targeted intelligently if we had the molecular insight into how the LptD/E and LptBCFG recognise and transport the LPS. My research is to use structural, molecular, biochemical and functional analyses to reveal the LPS transport mechanisms with the long-term vision of designing novel antibiotics combating multi-drug resistant bac teria. Within this overall goal, are four specific questions. 1). How does the LptD/E complex transport the LPS across outer membrane and precisely insert into the outer leaflet of the outer membrane? What are the crystal structures of the outer membrane protein LptD/E complex, in its oxidised form and in complex with LPS, and what is the molecular basis for the LPS transport in LptDE, and how this knowledge can be used for rational drug design? 2). At a molecular level, how does the inner membrane transporter complex LptBFG specifically extract the LPS molecules, passing them to LptC, and how does this process discriminate against phospholipids and lipoproteins? What is the gating mechanism of the LptBFG by exploring the open and closed forms of the transporter. Can we trap the LptBFG and LPS complex? 3). How to monitor the LPS transport in vitro and in vivo efficiently? Could we develop effective assays for functional studies and testing compound's activity?Can we set up the in vitro LPS transport assays? 4). Could we design and develop the probe tools or drugs to fight against multi-drug resistant bacteria based on our structural and functional studies?

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Grant Details

Amount Awarded 1703167
Applicant Surname Dong
Approval Committee Science Interview Panel
Award Date 2014-12-03T00:00:00+00:00
Financial Year 2014/15
Grant Programme: Title Investigator Award in Science
Internal ID 106121/Z/14/Z
Lead Applicant Prof Changjiang Dong
Partnership Value 1703167
Planned Dates: End Date 2020-04-27T00:00:00+00:00
Planned Dates: Start Date 2015-05-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England