Structural and molecular investigations of membrane-embedded pilus assembly nanomachines in Gram-negative bacterial pathogens

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Bacterial pili are cell surface appendages produced by bacterial pathogens. Pili are used by bacteria for recognition of and attachment to host tissues. Once attached to the host, the bacterium can start the process of infection. Therefore, pili are important means by which a pathogenic bacterium infects a host. Pili are large polymers of protein subunits termed pilins. Polymerisation of pilins into a mature pilus is mediated and orchestrated by macromolecular complexes embedded in the bacterial cell envelope. These complexes are large and often composed of many proteins. They function like machines and catalysts, grabbing individual pilins, catalysing their polymerisation, and facilitating their secretion through the bacterial envelope and their exposure at the bacterial cell surface. The major objective of this proposal is to investigate the structure and function of these machines, to understand how they work, and also, eventually, to find ways to inhibit them. Inhibiting the production of pili by bacteria would be very advantageous: i- without pili, the pathogenic bacterium cannot attach to its target tissue, and is therefore harmless; ii- because selective inhibition of pilus production is non-lethal, all the "good" bacteria which we naturally harbour in our bodies (the microbiome) and which play very beneficial roles will survive treatment. The concept of only inhibiting the pathogen while protecting the "good" bacteria from antibiotics action is a new concept in antimicrobials design, a concept that holds enormous promise for combating infectious diseases caused by bacteria. We are in a unique position to achieve these goals. Our track record is unique in the field of bacterial pathogenesis in general and pilus biogenesis in particular. Our structural biology work can be directly used to design small molecules capable of binding and disrupting crucial steps in the process of generating pili and secreting them.