Disrupting The Communication Between Cells To Inhibit The Virulence Of The Bacterium Bacillus Cereus

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The discovery of new antimicrobial agents is a major public health objective. In Bacillus cereus, a human pathogenic bacteria, virulence gene expression is synchronized and relies on the ability of the bacteria to communicate with each other. In Hayouka’s lab at the faculty of Agriculture, food and environment of the Hebrew University with their French colleagues have designed synthetic peptides capable of inhibiting the intercellular communication system involved in this process. This work, published on August 15th, 2018 in Chemical Communications magazine, opens the way to original perspectives to counter bacterial virulence.

In Gram positive bacteria, certain functions are regulated by intercellular communication systems called quorum sensing. In the pathogenic bacterium Bacillus cereus, responsible for food poisoning in humans, but also for nosocomial infections in immunosuppressed individuals, the PlcR-PapR system controls the transcription of the main virulence genes. In this system, PapR is the signaling peptide and PlcR is the transcriptional regulator. This is the key process of the pathogenicity of B. cereus that we and researchers at INRA have further explored.


Intercellular communication in Bacillus cereus
Intercellular communication in Bacillus cereus.
On the left, the signal peptide triggers the production of virulence factors in response to communication between bacterial cells (quorum sensing); on the right, synthetic signal peptides inhibit the production of virulence factors by disrupting communication between bacterial cells (quorum quenching).


Communicating between bacteria, from quorum sensing to quorum quenching

For several years, we have known that bacteria are able to communicate with each other and change their behavior according to their cell density through a process called quorum sensing or QS. This intercellular communication is based on chemical signals that bacteria synthesize and secrete to the external environment and that are recognized by neighboring bacteria. This leads to a synchronized community response through genetic regulatory mechanisms. The expression of virulence factors, sporulation, production of antifungals or antibiotics, biofilm formation are some of the functions regulated by QS.
The action of these signals and the functions controlled by QS can be attenuated or abolished by interfering with the signaling molecules (degradation, blocking or more). This will be called quorum quenching.

By Combining chemical, biochemical and genetic techniques, we have developed synthetic peptides derived from the PapR signaling peptide and demonstrated the ability of some of them to inhibit the PlcR-PapR system of B. cereus very efficiently and thus the expression of virulence factors by this pathogenic bacterium was abrogated as well.

These synthetic peptides do not affect bacterial growth but block the regulatory activity of PlcR when used in early growth phase. The team also showed that these peptides have a prolonged action during B. cereus growth.

These peptides are the first B. cereus quorum sensing system inhibitors that have ever been proposed. Their design and demonstration of their antagonistic function constitute a proof of concept and a key step in the identification and characterization of bacterial intercellular communication systems. We open up perspectives for developing innovative medical quenching quorum strategies that reduce or eliminate bacterial virulence rather than attempting to eliminate bacteria with antibiotics, or other antimicrobial agents, at the risk of selecting resistant microorganisms.

Reference
Turning off Bacillus cereus quorum sensing system with peptidic analogs
Avishag Yehuda, Leyla Slamti, Racheli Bochnik-Tamir, Einav Malach, Didier Lereclus and Zvi Hayouka
Chemical Communications, 2018

Scientific contact
Zvi Hayouka, zvi.hayouka@mail.huji.ac.il
Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Israel

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