Computational and native MS studies of B-Barrel outer membrane proteins and LPS biogenesis pathways: emerging structural targets for novel antibiotics

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Many disease causing bacteria such as Neisseria gonorrhoeae, Yersinia pestis, and Pseudomonas aeruginosa are known as Gram-negative. This means that these bacteria a surrounded by two hydrophobic barriers called the inner membrane (IM) and the outer membrane (OM) which are absolutely essential for the survival of the bacteria. These membranes are comprised by lipids which act to protect the bacteria against the outside environment as well as membrane proteins which perform many vital tasks for the cell. Membrane proteins themselves are of significant biomedical interest as they comprise more than 60 % of current drug targets. Currently there is an urgent need for the development of new drug therapies to fight the emergence of antibiotic resistant bacteria. This project will be studying two major systems which are vital in the maintenance of the OM in bacteria with the aim to characterise structural targets for the development of new drugs. The two systems which will be studied are the barrel assembly machine (or the BAM complex) and the Lpt system. The BAM complex resides in the OM and works to fold and insert outer membrane proteins (OMPs) into the OM, the Lpt systems shuttles a lipid known as LPS to the OM which is critical for the viability of the membrane. However, studying membrane proteins using conventional techniques is very challenging due to the strongly amphipathic nature (having both hydrophilic and hydrophobic parts) of membrane proteins as well as their dynamic interactions with their lipid environment. Therefore this project will use a native mass spectrometry technique known to maintain important protein lipid interaction in combination with computational molecular simulations to understand the dynamics of these systems. This project will be able to shed light on the structure and function of the BAM complex and the Lpt system in order to develop new and effective antibiotics for the future.Summary of BBSRC priority area:The work on membrane proteins directly targets the key BBSRC priority area of combatting antimicrobial resistance. New and accessible drug target are vital to combat the emerging threat of multidrug resistant bacteria. This project seeks to further characterise two critical bacterial biogenesis pathways; the B-barrel assembly machine and the Lpt system, by using native mass spectroscopy and molecular dynamics to gain in important sights to structure and function of these systems.