Molecular Mechanisms of anti-bacterial contact-dependent growth inhibition (CDI)

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Bacteria have evolved complex strategies to compete and communicate with one another. One important mechanism of inter-bacterial competition is mediated by contact-dependent growth inhibition (CDI) systems. CDI systems are found in a wide variety of Gram-negative bacteria, including many important human pathogens. CDI is mediated by the CdiB-CdiA family of two-partner secretion proteins. CdiB is an Omp85 outer-membrane protein that is required for the export and assembly of CdiA effector proteins onto the cell surface. CdiA binds to receptors on susceptible bacteria and then delivers its C-terminal toxin domain (CdiA- CT) into the target cell. CDI systems also encode CdiI immunity proteins, which bind the CdiA-CT and neutralize toxin activity to protect CDI+ cells from auto-inhibition. Remarkably, CdiA-CT sequences are highly variable between bacteria, as are the corresponding CdiI immunity proteins. Current analysis indicates that CDI systems encode at least 120 distinct CDI toxin-immunity families. This application proposes a combination of genetic, biochemical and ultrastructural analyses to gain mechanistic insights into cell-cell interactions and CdiA-CT toxin delivery during CDI. This research will significantly increase our understanding of the ecology and evolution of bacterial pathogens and could inform novel approaches to antimicrobial therapy.