Bacteria have evolved complex strategies to compete and communicate with one another. One important mechanism of inter-bacterial competition is contact-dependent growth inhibition (CDI). 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 the CdiA exoprotein 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. These systems also encode CdiI immunity proteins, which specifically bind to the CdiA-CT and neutralize toxin activity to protect CDI+ cells from auto-inhibition. CdiA-CT/CdiI sequences are highly variable, with >60 distinct toxin/immunity protein families recognized in bacterial genomes. We recently discovered that several CDI toxin/immunity proteins form higher order complexes with other cellular proteins. We hypothesize that these cellular protein function as permissive factors to activate CDI toxins inside target bacteria. The molecular mechanisms of CDI toxin activation are poorly understood, as are the broader physiological implications of toxin/permissive factor complexes. This application proposes a combination of genetic, biochemical and biophysical approaches to gain mechanistic insight into the network of protein-protein interactions that govern CDI. This research will significantly increase our understanding of the ecology and evolution of bacterial pathogens and could inform novel strategies for antimicrobial therapy.
Bacteria have evolved complex strategies to compete and communicate with one another. Contact-dependent growth inhibition (CDI) is one important mechanism of inter-bacterial competition found in a variety of Gram- negative bacterial pathogens. This proposal utilizes genetic, biochemical and structural analyses to gain mechanistic insights into CDI toxin activation. This research will significantly increase our understanding of the evolution and ecology of bacterial pathogens and could inform novel antimicrobial strategies.
| Cuthbert, Bonnie J; Burley, Kalistyn H; Goulding, Celia W (2018) Introducing the new bacterial branch of the RNase A superfamily. RNA Biol 15:9-12 |
| Michalska, Karolina; Quan Nhan, Dinh; Willett, Julia L E et al. (2018) Functional plasticity of antibacterial EndoU toxins. Mol Microbiol 109:509-527 |
| Kryshtafovych, Andriy; Albrecht, Reinhard; Baslé, Arnaud et al. (2018) Target highlights from the first post-PSI CASP experiment (CASP12, May-August 2016). Proteins 86 Suppl 1:27-50 |
| Michalska, Karolina; Gucinski, Grant C; Garza-Sánchez, Fernando et al. (2017) Structure of a novel antibacterial toxin that exploits elongation factor Tu to cleave specific transfer RNAs. Nucleic Acids Res 45:10306-10320 |
| Jones, Allison M; Garza-Sánchez, Fernando; So, Jaime et al. (2017) Activation of contact-dependent antibacterial tRNase toxins by translation elongation factors. Proc Natl Acad Sci U S A 114:E1951-E1957 |
| Benoni, Roberto; Beck, Christina M; Garza-Sánchez, Fernando et al. (2017) Activation of an anti-bacterial toxin by the biosynthetic enzyme CysK: mechanism of binding, interaction specificity and competition with cysteine synthase. Sci Rep 7:8817 |
| Batot, Gaëlle; Michalska, Karolina; Ekberg, Greg et al. (2017) The CDI toxin of Yersinia kristensenii is a novel bacterial member of the RNase A superfamily. Nucleic Acids Res 45:5013-5025 |
| Benoni, Roberto; De Bei, Omar; Paredi, Gianluca et al. (2017) Modulation of Escherichia coli serine acetyltransferase catalytic activity in the cysteine synthase complex. FEBS Lett 591:1212-1224 |
| Jones, Allison M; Low, David A; Hayes, Christopher S (2017) Can't you hear me knocking: contact-dependent competition and cooperation in bacteria. Emerg Top Life Sci 1:75-83 |
| Johnson, Parker M; Beck, Christina M; Morse, Robert P et al. (2016) Unraveling the essential role of CysK in CDI toxin activation. Proc Natl Acad Sci U S A 113:9792-7 |
