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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM117373-03
Application #
9511585
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Sledjeski, Darren D
Project Start
2016-08-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Santa Barbara
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
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