Bacterial pili—the hair-like surface appendages that pathogens use to latch onto human tissues—are assembled by protein nanomachines embedded in the bacterial cell envelope, and this project aims to reveal the atomic-level structure of those machines. Pili are essential for many bacterial infections, from urinary tract infections to pneumonia. Without them, bacteria cannot attach to host cells and cannot cause disease. Yet the molecular complexes that build pili remain poorly understood. This research will use structural biology techniques to map exactly how these machines grab individual pilin proteins, catalyse their polymerisation, and push the growing pilus through the bacterial membrane to the cell surface. If successful, this work could open a new route to antimicrobial drugs that work differently from traditional antibiotics. Instead of killing bacteria outright—which also wipes out beneficial gut microbes—a drug that blocks pilus assembly would simply disarm the pathogen. The "good" bacteria in the microbiome would survive, reducing side effects and slowing the spread of resistance. The researchers already have the structural data needed to begin designing small molecules that disrupt key steps in pilus production.
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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.
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