n → π* Interactions in N-Acyl Homoserine Lactone Derivatives and Their Effects on Hydrolysis Rates.

N-Acyl homoserine lactones (AHLs) mediate population-wide behavioral changes in Gram-negative bacteria through quorum sensing (QS), a process shown to regulate virulence, biofilm formation, and other phenotypes that impact human health. AHLs have been proposed to contain an n → π* interaction that reduces the molecules' susceptibility to signal inactivation via lactone hydrolysis. In this work, seven AHL derivatives were modeled via gas-phase DFT calculations, implicit solvent DFT calculations, and MD simulations. Each derivative was then synthesized and hydrolyzed to probe the relationship between the strength of the orbital interaction and hydrolysis rate. The data obtained support that an increase in n → π* energy (En→π*) correlates to a decrease in the hydrolysis rate constant ( kobs). Further, the observed variation in these rates demonstrates that AHL hydrolysis can be modified by manipulating steric and electronic effects that alter the electrophilicity of the lactone carbonyl. These results help to elucidate nature's choice of AHLs as agents of density-dependent bacterial communication and could inform the design of AHL-based quorum sensing modulators.