In gram-negative bacteria, N-acyl homoserine lactones (AHLs) are a class of small molecules that enable cell density-dependent chemical communication known as quorum sensing (QS). QS permits colony-wide gene expression resulting in a variety of phenotypes, like virulence factor production and biofilm formation, that can have an impact on human health. It has been proposed that the conformation of AHLs is influenced by n → π* interactions that reduce the molecules’ susceptibility to hydrolysis in an aqueous environment. To test this, seven AHL derivatives were modeled through gas-phase and implicit solvent DFT calculations and subjected to molecular dynamics (MD) simulations. Further, the AHL derivatives were synthesized so the rates of hydrolysis of each could be determined experimentally. Our combined data support that an increase in n → π* energy (E<sub>n→π*</sub>) correlates to a decrease in the hydrolysis rate constant (k<sub>obs</sub>). AHL hydrolysis can be modified by manipulating steric and electronic effects that alter the electrophilicity of the lactone carbonyl. These results could inform the design of AHL-based quorum sensing modulators and help to elucidate nature’s choice of AHLs as agents of density-dependent bacterial communication.

Assessing the influence of n → π* interactions on hydrolysis rates of n-acyl homoserine lactone derivatives

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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