Resistant-Prone Small Molecule Anti-Bacterial Antagonists and Targets for Anti-Bacterial Drug Development

Researchers at Princeton University, Department of Molecular Biology, have identified and synthesized small molecule antagonists that could serve as broad spectrum lead compounds for the disruption of quorum sensing in pathogenic Gram-negative bacteria. In proof of principle experiments, potent antagonist molecules have been developed that interfere with quorum sensing in several Gram-negative bacteria. It has been demonstrated that the administration of these quorum-sensing antagonist molecules to an animal, protect it from quorum-sensing-mediated killing by pathogenic bacteria¹.  

Bacteria communicate with one another using small molecules that they release into the environment.  These molecules, called autoinducers, travel from cell to cell. Bacteria have receptors on their surfaces that detect and respond to the build-up of the autoinducers which occurs in proportion to increasing cell-population density.  This process of bacterial communication is called ¿Quorum Sensing¿ and it allows bacteria to track their cell numbers and synchronize behavior on a population-wide scale. Bacterial behaviors controlled by quorum sensing are usually ones that are unproductive when undertaken by an individual bacterium acting alone but become effective when undertaken in unison by the group. For example, quorum sensing controls virulence, biofilm formation, sporulation, and the exchange of DNA. Thus, quorum sensing is a mechanism that allows bacteria to function as multi-cellular organisms.  Molecules that modulate quorum sensing have potential use as anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence. Similarly, the biosynthetic enzymes involved in autoinducer production and the autoinducer detection apparatuses are potential targets for novel anti-microbial drug design. In an analogous strategy, the artificial manipulation of beneficial quorum-sensing processes through pro-quorum sensing molecules could be used to improve industrial scale production of natural products.

Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity. Patent protection is pending.

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