Unravelling the rules of outer membrane protein folding: Opportunities for the design of new antibacterial strategies

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The folding and assembly of outer membrane proteins (OMPs) is essential to build the cell wall of gram-negative bacteria. How the sequences of OMPs enable their folding into the bacterial OM remains unknown, nor is it understood how the essential B-barrel assembly machinery (BAM), recognises folding OMPs and inserts them into the outer membrane (OM). Understanding OMP folding is not only of immense fundamental interest, but is translationally important as targeting this pathway could lead to new strategies to combat antibiotic resistance in gram-negative pathogens. Building on a recent collaboration with David Baker (Seattle) (Science 2021), we have successfully designed the first synthetic trans membrane beta barrel protein, providing a unique opportunity to compare the folding mechanisms of de novo designed proteins with their naturally evolved counterparts in vitro, and assisted/unassisted by BAM.This project will determine:(i) how the sequence of OMPs enables efficient folding to their highly-stable beta-barrel structures in vitro; (ii) which sequence/structural motifs of OMPs are recognised by BAM;(iii) how the cellular machinery recognizes OMPS and targets them to BAM for folding into the OM. The results will be new fundamental knowledge of how OMPs fold, new insights into how BAM recognises OMPs and potentially, new routs of combat antibiotic resistance by targeting OMP folding.