GEN Exclusives

More »

GEN News Highlights

More »
Apr 21, 2011

Investigators Identify Strategies to Block Quorum Sensing in Pathogenic Bacteria

  • Researchers report on new discoveries relating to the mechanisms of bacterial quorum sensing, a communication strategy used by many bacteria including pathogenic species to control and coordinate collective behavior and the expression of virulence factors. Their work also led them to identifying a method to block this pathway.

    The research, by a team at Princeton University’s department of molecular biology and the Howard Hughes Medical Institute, is detailed in Molecular Cell in a paper titled “A Strategy for Antagonizing Quorum Sensing.” 

    Quorum-sensing bacteria communicate via small molecules called autoinducers, explain Princeton’s Frederick M. Hughson, Ph.D., and colleagues. Gram-negative bacteria commonly use acyl-homoserine lactone molecules (AHLs) as autoinducers, and different species employ one of two mechanisms to detect them. One of these, found in many bacteria, uses cytoplasmic LuxR-type transcription factor proteins as the autoinducer receptor. Small molecule quorum sensing antagonists have previously been identified, but their mechanisms of action have yet to be defined. 

    The researchers used a battery of structure-function techniques to define a mechanism underlying antagonism of LuxR-type receptors. The studies built on their previous work that demonstrated the ability of a chlorolactone LuxR antagonist to prevent the human pathogen Chromobacterium violaceum from killing Caenorhabditis elegans.

    In the strain of Chromobacterium violaceum bacterium they focused on, autoinducers bind to the LuxR-type transcription factor protein CviR. LuxR-type proteins are homodimers, each monomer of which consists of two domains, a ligand-binding domain (LBD) and a DNA-binding domain (DBD).

    Structure-function studies with natural and synthetic ligands to CviR, including their chlorolactone antagonist, demonstrated that the transcription factor CviR was potently blocked by molecules that bind in place of the native acylated homoserine lactone autoinducer, as long as antagonist binding induced a closed conformation incapable of binding to DNA. Effectively, the structure of antagonist-bound CviR was such that the DBD of each monomer was positioned below the LBD of the opposite monomer in a crossed-domain conformation that masked the opposing ligand-binding sites. 

    The researchers suggest this binding site competition could be exploited to block quorum sensing recognition by LuxR family receptors in one of two ways. The first strategy, demonstrated by the Princeton and Howard Hughes researchers, is to identify ligands that bind in place of the autoinducer and that—to a greater extent than the autoinducer—favor an inactivating LBD-DBD interaction.

    A second related approach would be to identify molecules that bind to preformed LuxR-autoinducer complexes in such a way as to stabilize closed conformations. However, they note that to the best of their knowledge no examples of this latter type of small molecule antagonist has been reported. 


Add a comment

  • You must be signed in to perform this action.
    Click here to Login or Register for free.
    You will be taken back to your selected item after Login/Registration.

Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...
More »

GEN Poll

More » Poll Results »

Alzheimer's Therapies

Do you think an effective treatment for Alzheimer’s will be found within the next 10–15 years?