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 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. CDI systems also encode CdiI immunity proteins, which specifically bind to the CdiA- CT and neutralize toxin activity, thereby protecting 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.

Public Health Relevance

Bacteria have evolved complex strategies to compete and communicate with one other. Contact-dependent growth inhibition (CDI) is one important mechanism of inter-bacterial competition, and these systems are distributed widely amongst Gram-negative bacteria, including several important human pathogens. This application proposes a combination of molecular genetic, biochemical and ultra-structural approaches to gain insights into the mechanisms that control cell-cell interaction and toxin delivery during CDI. This research will significantly increase our understanding of the ecology and evolution of bacterial pathogens and could inform the development of novel antimicrobial therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM117930-02
Application #
9207766
Study Section
Special Emphasis Panel (ZRG1-GGG-E (02)M)
Program Officer
Deatherage, James F
Project Start
2016-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$333,050
Indirect Cost
$109,994
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
Beck, Christina M; Willett, Julia L E; Cunningham, David A et al. (2016) CdiA Effectors from Uropathogenic Escherichia coli Use Heterotrimeric Osmoporins as Receptors to Recognize Target Bacteria. PLoS Pathog 12:e1005925