Role of a novel auto-protease domain in antibacterial toxin delivery

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Project summary Contact-dependent growth inhibition (CDI) is an important mechanism of inter-bacterial competition 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, which are thought to assemble as a binary complex on the cell surface. CdiA forms a thin filament to projects away from the inhibitor cell to bind to receptors on susceptible bacteria. After binding receptor, CdiA delivers its C-terminal toxin domain (CdiA-CT) into the target cell. CDI systems also encode CdiI immunity proteins, which specifically bind to the CdiA-CT and neutralize toxin activity to protect the cell from auto-inhibition. CdiA-CT/CdiI sequences are extraordinarily variable, with >130 distinct toxin/immunity protein sequence types recognized in bacterial genomes. CdiA-CT toxins are modular and can be exchanged between CdiA proteins to generate functional chimeras. These observations indicate that many different kinds of toxic cargo can be delivered into the cytoplasm of target bacteria. This application seeks to determine the molecular and structural underpinnings that enable this remarkable functional plasticity. We will use a combination of molecular genetic, biochemical and structural approaches to gain insight into the functional interactions between the constituent domains of CdiA. This research will significantly increase our mechanistic understanding of CdiA function and could inform novel strategies for antimicrobial therapy.