Traditional therapeutics to treat bacterial infections have given rise to multi-drug resistant pathogens, which pose a major threat to human and animal health. Currently, antibiotics work by either killing or inhibiting the growth of bacteria, allowing the evolution of resistant strains. As such, it is crucial to find ways to treat bacterial infections without promoting resistance. One alternative is through the inhibition of quorum sensing (QS) pathways, which are bacteria cell-cell communication processes. Quorum sensing is mediated through the production and detection of small molecules called autoinducers. Once a quorum is detected, the bacteria express certain genes necessary for infection of a host, including virulence factor production, biofilm formation, and swarming. Previously, our lab has shown that ethyl β-keto esters containing a substituted phenyl ring are capable of interfering with QS by binding to the bacteria’s receptor and blocking the autoinducer. More recently, we have synthesized a new library of β-keto esters through a transesterification reaction, replacing the ethyl ester with various substituted benzyl esters. This new panel of compounds has also been tested using a broth dilution assay in a wild type strain of Vibrio harveyi for the ability to inhibit luminescence, a phenotype controlled through QS, and IC50s were calculated. Several of these diaryl β-keto esters have demonstrated a 3-fold increase in activity with an average IC50 of 5 μM. Expansion of the β-keto ester panel will enable us to obtain more insight into the structure–activity relationships needed to allow for the development of novel anti-virulence agents.

Transesterification and bacterial quorum sensing inhibition of β-keto esters

255th National Meeting (2018)

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